N-{2-[4-amino-2-(ethoxymethyl)-1h-imidazo-[4,5-c]-quinolin-1-yl]-1,1-dimethylethyl}-methanesulfonamide and pharmaceutical compositon based on said compound

FIELD: chemistry.

SUBSTANCE: invention relates to a new derivative of sulfonamide substituted imidazoquinolines, and specifically to N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-c]-qunolin-1-yl]-1,1-dimethylethyl}-methanesulfonamide and its pharmaceutically acceptable salts, as well as to a pharmaceutical composition based on this compound.

EFFECT: invention also relates to a method of inducing biosynthesis of cytokines in an animal organism and methods of treating viral and oncological diseases in animals using said compound and pharmaceutical composition based on said compound.

5 cl, 1 tbl, 39 ex

 

Scope

The present invention extends to imidazoquinolines connection with sulfonamidnuyu the substituent in position 1 and to pharmaceutical formulations containing such compounds. Another aspect of the present invention associated with the use of these compounds as immunomodulators, for inducing the biosynthesis of cytokines in animals and for the treatment of diseases, in particular viral and cancer.

Background of the invention

In the first reliable message system 1H-imidazo-[4,5-C]-quinoline ring, Backman et al., J. Org. Chem. 15, 1278-1284 (1950), describes the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo-[4,5-C]-quinoline with a view to possible application of the antimalarial agent. Subsequently made numerous reports on the synthesis of various substituted 1H-imidazo-[4,5-C]-quinoline. For example, in the work of Jain et al., J. Med. Chem. 11, pp.87-92 (1968) reported the synthesis of a substance 1-[2-(4-piperidyl)-ethyl]-1H-imidazo-[4,5-C]-quinoline as a potential anticonvulsant and cardiovascular agent. In addition, Baranov et al., Chem. Abs. 85, 94362 (1976), reported several 2-accomidate-[4,5-C]-quinoline, and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981)reported some 2-accomidate-[4,5-C]-quinoline.

It was later discovered that some of 1H-imidazo-[4,5-C]-quinoline-4-amines and their 1 - and 2-substituted derivatives can be used as antiviral is usnih, bronchodilatory and immunomodulating drugs. They are described in particular in patents U.S.№ 4689338; 4698348; 4929624; 5037986; 5268376; 5346905 and 5389640, which are incorporated herein by reference.

Continues to generate interest system imidazoquinolines rings, as you can see, for example, in documents WO 98/30562, EP 894797 and WO 00/09506. Thus, in the patent EP 894797 describes amazonienne imidazopyridine compounds, which are disclosed as substances that can have a modulating effect on the immune response, and in WO 00/09506 disclosed imidazoquinolines substances which contain sulfonamidnuyu replacement group in which the nitrogen sulfonamida is part of a saturated heterocyclic ring. Despite these attempts, however, a need remains in the search of new compounds able to modulate the immune response by induction of the biosynthesis of cytokines or through other mechanisms.

Brief description of the invention

We discovered a new class of compounds that can induce the biosynthesis of cytokines in animals. Thus, this invention is compounds corresponding to the formula I:

where R, R1and R2are determined as described below.

Compounds corresponding to formula I, can act as modulators of the immune response due to their SP is the ability to induce the biosynthesis of cytokines and on the other hand, to modulate the immune response when introduced animals. This makes these compounds suitable for the treatment of various conditions, such as viral diseases and tumors that are responsive to such changes in the immune response.

In one of the embodiments of the invention discussed compounds are selected from the group consisting of the following substances:

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

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

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

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

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

N-[4-{4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide;

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

N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide;

N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]benzosulfimide;

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

N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}benzosulfimide;

N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}methanesulfonamide;

N-[8-(4-amino-2-butyl-1H-it is data-[4,5-C]-quinoline-1-yl)octyl]methanesulfonamide;

N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide;

N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-4-methylbenzenesulfonamide;

N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide;

N-[8-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]benzosulfimide;

N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}benzosulfimide;

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

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

N-[8-(4-amino-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]methanesulfonamide;

N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-propyl}-4-methylbenzenesulfonamide;

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

N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide;

N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-2,2-dimethylpropyl}methanesulfonamide;

N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-propyl}-5-(dimethylamino)naphthalene-1-sulfonamide;

N-[3-(4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-methanesulfonamide;

N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide;

N-{3-[4-amino-2-(ethoxymethyl)-6,7,8,9-then it is carbonated the ro-1H-imidazo-[4,5-c]quinoline-1-yl]propyl}methanesulfonamide;

N-{3-[4-amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl}methanesulfonamide;

N-{4-[4-amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl]butyl}methanesulfonamide;

N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide hydrochloride;

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

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

1-[4-(1,1-dioxothiazolidine-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine;

2-butyl-1-[4-(1,1-dioxothiazolidine-2-yl)butyl]-1H-imidazo-[4,5-C]-quinoline-4-amine;

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

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

1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine and

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

or pharmaceutically acceptable salt of these substances.

In a particularly preferred implementation of this invention in such a substance or salt is N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-C]-quinoline-1-yl]-1,1-dimethylethyl}methanesulfonamide or pharmaceutically acceptable salt of this substance. In addition to the formula and low toxicity of this compound possesses unexpectedly high the activity against induction of interleukin IL-12, comparable with interferon-(α)-inducing activity.

In addition, the invention presents a pharmaceutical composition containing a therapeutically effective amount of a substance or a salt corresponding to the formula I or the above examples, and methods induction of the biosynthesis of cytokines in the body of an animal, treating a viral infection and/or treatment of cancer in the body of an animal by introducing into the animal an effective amount of a substance corresponding to the formula I or the above examples, or its salt.

In addition, the methods of synthesis of compounds of the formula I, and intermediates used in the synthesis of these compounds.

Detailed description of the invention

As mentioned above, the present invention is represented by compounds corresponding to the formula I:

in which R1- -alkyl-NR3-SO2-X-R4-alkenyl-NR3-SO2-X-R4or-alkyl-NR6-SO2-R7 ;

X is a covalent bond or-NR5-;

R4- aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of the following residues:

- alkyl;

- Elke the sludge;

- aryl;

- heteroaryl;

- heterocyclyl;

- substituted aryl;

- substituted heteroaryl;

- substituted heterocyclyl; -O-alkyl;

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

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

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

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

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

-COOH;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

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

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

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

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

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

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

-(alkyl)0-1-NR3R3;

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

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

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

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

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

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

-N3;

- halogen;

- haloalkyl;

- haloalkoxy;

WITH haloalkoxy;

-NO2;

-CN;

-HE;

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

R2is selected from the group consisting of the following:

is hydrogen;

- alkyl;

alkenyl;

- aryl;

- alseny aryl;

- heteroaryl;

- substituted heteroaryl;

- alkyl-O-alkyl;

- alkyl-O-alkenyl and

- alkyl or alkenyl substituted by one or more substituents selected from the group that includes the following balances:

-HE;

- halogen;

-N(R3)2;

-CO-N(R3)2;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

- aryl;

- substituted aryl;

- heteroaryl;

- substituted heteroaryl;

- heterocyclyl;

- substituted heterocyclyl;

-CO-aryl;

-CO-(substituted aryl);

-CO-heteroaryl and

-CO-(substituted heteroaryl);

each R3independently selected from the group including hydrogen, C1-10alkyl;

R5is selected from the group consisting of hydrogen and C1-10the alkyl, or R4and R5can be connected with the formation of a 3-7-membered heterocyclic or substituted heterocyclic ring;

R6is selected from the group consisting of hydrogen and C1-10of alkyl;

R7is selected from the group consisting of hydrogen and C1-10of alkyl, where R6and R7connected with the formation of a 3-7-membered heterocyclic or substituted heterocyclic ring;

n is a number from 0 to 4, and each presents the remainder R is independently selected from the group comprising From1-10-alkyl, C1-10-alkoxy, halogen and trifluoromethyl, Il the pharmaceutically acceptable salts of these substances.

Synthesis of substances

Imidazoquinolines presented in this invention can be obtained according to Reaction scheme I where R, R1, R2and n are defined as described above.

At stage (1) of Reaction scheme I, a 4-chloro-3-nitroquinoline corresponding to the formula II is reacted with an amine corresponding to the formula R1NH2where R1is determined, as described above, with the formation of 3-nitroanilin-4-amine corresponding to the formula III. This reaction can be carry out by adding the amine to a solution of the substance corresponding to the formula II, in a suitable solvent, such as chloroform or dichloromethane, and optional when heated. Many quinoline, corresponding to the formula II are known compounds (see, for example, U.S. patent 4689338 and references cited herein).

At stage (2) of Reaction scheme I 3-nitroanilin-4-amine corresponding to the formula III, is restored by the formation of a quinoline-3,4-diamine corresponding to the formula IV. Preferably, the recovery was conducted using a standard heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. This reaction can be performed in a standard way on the Parr apparatus in a suitable solvent, such as isopropyl alcohol or toluene.

At stage (3) the Reaction is ionic scheme I a quinoline-3,4-diamine, corresponding to the formula IV is reacted with a carboxylic acid or equivalent with the formation of 1H-imidazo-[4,5-C]-quinoline of the formula V. In the number of substances equivalent to carboxylic acids include halide acids, orthoepy and 1,1-dialogshell-alkanoate. Carboxylic acid or equivalent is selected such that the reaction turned out the required R2- Deputy in the substance corresponding to the formula V. for Example, triethyl-ortho-formate will give the substance in which R2is hydrogen, and triethyl-ortho-acetate will give the substance in which R2is a methyl group. 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 heating, sufficient to remove any alcohol or water, which are byproducts of this reaction.

At step (4) of Reaction scheme I 1H-imidazo-[4,5-C]-quinoline, corresponding to the formula V, is oxidized with the formation of 1H-imidazo-[4,5-C]quinoline-5N-oxide corresponding to the formula VI using standard oxidizing agent that can lead to the formation of N-oxides. The preferred conditions for the reaction is the reaction of a solution of a substance corresponding to the formula V in chloroform with 3-chloroperoxybenzoic acid under normal conditions.

On e the up (5) of Reaction scheme I 1H-imidazo-[4,5-C]quinoline-5N-oxide, the corresponding formula VI, miniroot with the formation of 1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to the formula VII, which is a subgenus of substances corresponding to the formula I. Step (5) includes (i) conducting a reaction of a substance corresponding to the formula VI, with allermuir agent, and then (ii) reaction of the product with aminimum agent. Part (i) of step (5) involves the reaction of N-oxide corresponding to the formula VI, with allermuir agent. Among the suitable alleluya agents include alkyl - or aryl-sulfonyl-chlorides (for example, benzazolyl-chloride, methanesulfonyl-chloride, p-toluensulfonyl-chloride). Arylsulfonyl-chlorides are preferred. pair-Toluensulfonyl-chloride is most preferred. Part (ii) of step (5) comprises the reaction product of part (i) with excess amineralo agent. Among the suitable mineralsa agents include ammonium (for example, in the form of ammonium hydroxide) and ammonium salts (e.g. ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Preferred is ammonium hydroxide. The reaction is preferably conducted by dissolving N-oxide corresponding to the formula VI in an inert solvent, such as dichloromethane, are added to the solution amineralo agent, and then slowly add Alliluyeva agent. The product or its pharmaceutically acceptable salt can be selected with the COI is whether the standard methods.

In an alternative embodiment, step (5) can be done through (i) the reaction of N-oxide corresponding to the formula VI, with isocyanate, and then (ii) hydrolysis of the resulting product. Part (i) involves the reaction of N-oxide with an isocyanate in which the isocyanate group bound to a carboxyl group. In a preferred isocyanates include trichloracetic-isocyanate and aroyl-isocyanates, such as benzoyl-isocyanate. The reaction of the isocyanate with N-oxide is carried out in practically anhydrous conditions by adding the isocyanate to a solution of N-oxide in an inert solvent, such as chloroform or dichloromethane. Part (ii) involves the hydrolysis of the product from part (i). This hydrolysis can hold standard methods, for example by heating in the presence of water or a lower alcohol, optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide.

A reaction scheme I

Substances, which are presented in the present invention, and in which the substituent R1contains a sulfonamide, can also be obtained according to reaction Scheme II, in which R, R1, R4and n are defined as described above, a m is a number from 1 to 20.

In reaction Scheme II aminoalkylsilanes 1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula VIII is reacted with sulfonyl-chloride, correspond to the named formula IX, with the formation of compounds corresponding to the formula X, which describes a subgenus of compounds of formula I. the Reaction can be conducted at room temperature in an inert solvent, such as dichloromethane, in the presence of a base, for example pyridine or N,N-diisopropylethylamine. Many 1H-imidazo-[4,5-C]-quinoline-4-amines corresponding to formula VIII are known substances are described, for example in U.S. patent 6069149 (Namba); others can be easily obtained by using known methods of synthesis. Many sulfonyl-chlorides, the corresponding formula IX are commercially available; others can be easily obtained by using known methods of synthesis. Received the product or its pharmaceutically acceptable salt can be distinguished using standard methods.

A reaction scheme II

Compounds that are presented in this invention and in which the substituent R1contains a sulfonamide, can also be obtained according to reaction Scheme III, in which R, R2, R4and n are defined as described above, a m is a number from 1 to 20.

In reaction Scheme III aminoalkylsilanes 1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula VIII is reacted with a sulfonic anhydride corresponding to the formula XI, with the formation of compounds, sootvetstvuyuschego the formula X, which describes a subgenus of compounds of formula I. the Reaction can be conducted at room temperature in an inert solvent, such as dichloromethane, in the presence of a base such as pyridine or N,N-diisopropylethylamine. Alternatively, the reaction can be conducted at room temperature in acetonitrile. Many of sulfonic anhydrides corresponding to the formula XI are commercially available; others can be easily obtained by using known methods of synthesis. The product or its pharmaceutically acceptable salt can be distinguished using standard methods.

A reaction scheme III

Tertiary sulfonamides presented in this invention can be obtained according to Reaction scheme IV, in which R, R2, R3, R4and n are defined as described above, a m is a number from 1 to 20.

In reaction Scheme IV 1H-imidazo-[4,5-C]-chinoline-sulfonamide corresponding to the formula X is reacted with a halide corresponding to the formula XII, with the formation of the compound corresponding to formula XIII, which describes a subgenus of compounds of formula I. the Reaction can be conducted at room temperature by adding sodium hydride to a solution of the substance corresponding to the formula X, in N,N-dimethylformamide, followed by adding the Alida. Many halide corresponding to formula XII are commercially available; others can be easily obtained by using known methods of synthesis. Received the product or its pharmaceutically acceptable salt can be distinguished using standard methods.

A reaction scheme IV

Compounds that are presented in this invention and in which R1contains sulfa group, can be obtained according to Reaction scheme V, where R, R2, R4, R5and n are defined as described above, a m is a number from 1 to 20.

At stage (1) of reaction Scheme V aminoalkylsilanes 1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula VIII is reacted with sulfurylchloride with the formation in situ of sulfhemoglobin corresponding to the formula XIV. The reaction can be conducted by adding a solution of sulfurylchloride in dichloromethane to a solution of the substance corresponding to the formula VIII, in dichloromethane in the presence of one equivalent of 4-(dimethylamino)pyridine. This reaction is preferably carried out at low temperature (-78°C). Optional, after the addition finished, the reaction mixture can be heated to room temperature.

At stage (2) of reaction Scheme V amine corresponding to the formula R5R4NH, reacts with sulfhemoglobin, sootvetstvuyuschim formula XIV, with the formation of 1H-imidazo-[4,5-C]-hyalinella corresponding to the formula XV, which describes a subgenus of compounds of formula I. the Reaction can be conducted by adding a solution containing 2 equivalents of amine and 2 equivalents of triethylamine in dichloromethane to the reaction mixture obtained in step (1). The addition is preferably carried out at low temperature (-78°C). After the addition completed, the reaction mixture can be heated to room temperature. Received the product or its pharmaceutically acceptable salt can be distinguished using standard methods.

The reaction scheme V

Tetrahydroisoquinoline presented in this invention can be obtained according to Reaction scheme VI, where R2, R3, R4and R5determined, as described above, a m is 1-20.

At stage (1) of reaction Scheme VI aminoalkylsilanes 1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula XVI, is restored by education aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to the formula XVII. Preferably, the restoration was carried out by the suspension or dissolution of the substance corresponding to the formula XVI, in triperoxonane acid, adding catalytic amounts OK the IDA platinum (IV) with subsequent treatment of the mixture with hydrogen at high pressure. This reaction can be performed in a standard way on the Parr apparatus. Received the product or its salt can be distinguished using standard methods.

In step (2A) of reaction Scheme VI aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula XVII, reacts with the formation of compounds corresponding to the formula XVIII, which describes a subgenus of compounds of formula I. If R3is hydrogen, the reaction can be carried out in one stage in accordance with the methods described in the above reaction Schemes II and III using tetrahydroisoquinoline corresponding to formula XVII, instead of imidazoquinolines corresponding to formula VIII. If R3Deputy other than hydrogen, the reaction can be carried out in two stages, where one stage is carried out in accordance with the methods of Reaction schemes II and III, and the second stage is carried out in accordance with the method of Reaction IV using tetrahydroisoquinoline analog imidazoquinolines. Received the product or its pharmaceutically acceptable salt can be distinguished using standard methods.

At step (2b) of reaction Scheme VI aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to formula XVII, reacts with the formation of compounds corresponding to the formula XIX, to the which describes the subgenus of compounds, corresponding to the formula I. the Reaction can be carried out in accordance with the method described in Reaction scheme V, using tetrahydroisoquinoline corresponding to formula XVII, instead of imidazoquinolines corresponding to formula VIII. Received the product or its pharmaceutically acceptable salt can be distinguished using standard methods.

The reaction scheme VI

Tetrahydroisoquinoline presented in this invention can be obtained according to Reaction scheme VII, where R, R2, R3, R4, R5and n are defined as described above, a m is a number from 1 to 20.

At stage (1) of reaction Scheme VII 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-chinoline-tert-BUTYLCARBAMATE corresponding to formula XX, is subjected to hydrolysis with the formation of aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine corresponding to the formula XXI. The reaction can be conducted by dissolving the substances corresponding to the formula XX, in a mixture triperoxonane acid and acetonitrile and stirring at room temperature. Alternatively, the substance corresponding to the formula XX can be mixed with diluted hydrochloric acid and heat on a steam bath. Tetrahydro-1H-imidazo-[4,5-C]-chinoline-tert-BUTYLCARBAMATE corresponding to formula XX can be obtained and the use of the method of synthesis, disclosed in U.S. Patent 5352784 (Nikolaides). Received the product or its salt can be distinguished using standard methods.

Steps (2A) and (2b) can be performed in the same way, which is indicated in Reaction scheme VI.

The reaction scheme VII

Some compounds corresponding to formula I, can be easily obtained from other compounds of formula I. for Example, compounds where the substituent R4contains choralcelo group can react with the amine with the formation of R4-Deputy, substituted secondary or tertiary amino group; a substance in which the substituent R4contains a nitro-group, can be restored with the formation of matter in which the substituent R4contains a primary amine.

When used in the context of the present document, the terms "alkyl", "alkenyl", "quinil" and the prefix "ALK-" include remotemachine and branched groups, and groups with a cyclic structure, that is, cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, and alkeneamine and alkyline groups contain from 2 to 20 carbon atoms. A preferred group of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic, and preferably, the number and the Ohm carbon in the ring ranged from 3 to 10. As examples of cyclic groups can be called cyclopropyl, cyclopentyl, cyclohexyl and substituted.

The term "haloalkyl" includes groups, which contain as substituents one or more halogen atoms, including groups in which all of the available hydrogen atoms replaced by halogen atoms. This is also true for groups whose names contain the prefix "Halaal-". As examples haloalkyl groups include chloromethyl, trifluoromethyl, etc.

The term "aryl" when used within this document includes carbocyclic aromatic ring or rings. As examples of aryl groups can be called phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or rings that contain at least one heteroatom (e.g., O, S, N) in the ring. Suitable heteroaryl groups are furyl, thienyl, pyridyl, chinoline, tetrazolyl, imidazo, pyrazolo, triazolo, oxazolo and so on.

The term "heterocyclyl" includes non-aromatic rings or rings that contain at least one ring heteroatom (e.g., O, S, N). As examples of heterocyclic groups can be called pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidine, piperazinil, thiazole is dinil, imidazolidinyl and so on.

Unless otherwise specified, the terms "substituted cycloalkyl", "substituted aryl", "substituted heteroaryl" and "substituted heterocyclyl" indicates that the ring or rings are optionally substituted by one or more substituents selected from the group including alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloalkaliphilic, haloalkoxy (for example, triptoreline), nitro, alkylsulphonyl, alkenylboronic, arylcarbamoyl, heteroarylboronic, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclic, heteroseksualci, nitrile, alkoxycarbonyl, alkanoyloxy, alkanity, and in the case of cycloalkyl and heterocyclyl - oxo.

The structural formulas for the substances in the present invention, some of the links are represented by dashed lines. These lines indicate that the relationship depicted by the dashed line, may be present or absent. In this regard, the compounds corresponding to formula I, can be either imidazoquinolines substances or tetrahydroisoquinolinium substances.

The invention extends to all substances referred to in this document, in any pharmaceutically acceptable forms, including isomers, as diastereomers and enantiomers, salts, solvate, polymorph modifications the AI and so on.

Pharmaceutical composition and biological activity

Pharmaceutical compositions provided in the present invention contain a therapeutically effective amount of a substance corresponding to the formula I, in combination with a pharmaceutically acceptable carrier.

When used in this document, the term "therapeutically effective amount" refers to an amount of a substance that is sufficient to provide a therapeutic action, such as the induction of cytokines, antitumor activity and/or antiviral activity. Although the exact number of active substances used in the pharmaceutical compositions provided in the present invention, will vary depending on factors that are well known to experienced professionals, including physical and chemical nature of the substance and nature of media and the assigned mode of administration, however, it is believed that the compositions presented in the present invention, contain enough active ingredient to create a dose from about 100 ng/kg to about 50 mg/kg, preferably from about 10 mg/kg to about 5 mg/kg weight of a subject. You can use any standard dosage forms, such as tablets, pills, formulas for parenteral administration, syrups, creams, ointments, AE is ozolinya formula, transdermal patches, transmucosal patches and others.

In experiments conducted in accordance with the tests presented below, it is shown that the substances in the present invention, cause the production of some cytokines. These results indicate that these substances can be used as modulators of the immune response, which can enhance the immune response in a variety of ways, making them suitable for the treatment of several diseases.

Among the cytokines, the synthesis of which can be induced by introduction substances, present in the framework of the present invention generally include interferon-α (IFN-α) and factor-α tumor necrosis (TNF-α)and interleukins (IL). Cytokines, the biosynthesis of which the tumor necrosis factor-α agents in the present invention include IFN-α, TNF-α, IL-1, 6, 10 and 12 and other cytokines. Among many other effects of cytokines inhibit the multiplication of viruses and tumor cell growth, making these compounds useful for the treatment of viral diseases and tumors.

In addition to the ability to stimulate the production of cytokines substances presented in the present invention, have an impact on other aspects of the innate immune response. For example, they can stimulate the activity of natural killer cells - the effect which can be associated with the induction of cytokines. These compounds can also activate macrophages, which in turn increases the secretion of nitric oxide and the production of additional cytokines. In addition, the compounds can induce proliferation and differentiation of b-lymphocytes.

The compounds presented in this invention, is also affected by the acquired immune response. For example, although it is believed that there is no direct effect on T cells or direct induction of T-cell cytokines, however, with the introduction of these substances in the production of the cytokine IFN-γ by T-helper type 1 (The1) is induced indirectly and the production of cytokines IL-4, IL-5 and IL-13 T-helper type 2 (The2) is suppressed. This activity means that the data connection can be used to treat diseases that require positive regulation of Th1 response and/or negative regulation of the Th2 response. From the point of view of the ability of compounds of the formula Ia, to suppress Th2-immune response, it can be assumed that these compounds applicable in the treatment of allergic diseases such as atopic dermatitis, asthma, allergies and allergic rhinitis, systemic lupus erythematosus; they can be used as an adjuvant to vaccines for cellular immunity and, apparently, as a remedy for the treatment of recurrent fungal C is of disease and chlamydia.

Modulating effect on the immune response caused by these substances makes them useful for the treatment of a wide range of diseases. Due to their ability to induce the production of cytokines such as IFN-α and/or TNF-α, the compounds are particularly useful for the treatment of viral diseases and tumors. This immunomodulating activity suggests that the matter presented in this invention can be used to treat diseases including, but not limited to, such as viral diseases, including genital warts; common warts; keratotic warts; hepatitis b; hepatitis C; simple herpes virus type I and type II; molluscum contagiosum; HIV; CMV; varicella zoster virus; intraepithelial tumor, such as intraepithelial tumor of the cervix; the defeat of the human papilloma virus (HPV) and associated tumors, fungal infections, such as candidiasis, aspergillosis, and cryptococcal meningitis; oncologic diseases, for example, basal cell carcinoma, leukemia, hairy cell, Kaposi's sarcoma, renal carcinoma cells, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma and other forms of cancer, parasitic diseases, such as pneumocystosis, cryptosporidiosis, histoplasmosis, Tox is plasmas, Trypanosoma infection, leishmaniasis and bacterial infections, such as tuberculosis and mycobacteriosis in birds. Other diseases or conditions that can be treated using the substances presented in the present invention, includes eczema; eosinophilia; essential thrombocythemia; leprosy; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; bowenoid papules, as well as to improve and stimulate the healing of wounds, including chronic wounds.

In this regard, the invention provides a method of induction of the biosynthesis of cytokines in the body of an animal, comprising introducing an effective amount of a substance corresponding to the formula I, in the body of the animal. The amount of a substance effective for the induction of the biosynthesis of cytokines, is a quantity sufficient to stimulate one or more types of cells, such as monocytes, macrophages, dendrobiinae cells and b-cells, to produce such a quantity of one or more cytokines, such as IFN-α, TNF-α, IL-1, 6, 10 and 12, which exceeds the initial level of such cytokines. The exact amount will vary depending on factors known to skilled specialists, however, the expected dose is from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg In addition, the invention provides a method of treatment of viral infections in animals and method of treatment of oncological diseases in animals, including the introduction of an effective amount of a substance corresponding to the formula I, in the body of the animal. The amount effective for the treatment or suppression of viral infection, is the number that causes the reduction of one or more manifestations of viral infections, such as viral lesions, viral load and speed of production of the virus, and mortality compared to control animals not treated with this substance. The exact amount will vary depending on factors known to skilled specialists, however, the expected dose is from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg quantity of a substance effective for the treatment of tumors, is the number that causes a decrease in tumor size or number of lesions. And in this case, the exact amount will vary depending on factors known to skilled specialists, however, the expected dose is from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg

Hereinafter the invention will be described in the following examples, which are presented for purposes of illustration and not under asomewhat any restrictions on the scope of the invention.

Example 1

N-[4-(4-Amino-2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide

The triethylamine (1,18 ml, 8.5 mmol) is added to a mixture of 1-(4-aminobutyl)-2-ethyl-1H-imidazo-[4,5-C]-quinoline-4-amine (2.00 g, 7.1 mmol) and chloroform (200 ml). The resulting solution was cooled in an acetone/ice bath for 10 minutes. Benzazolyl-chloride (0,90 ml, 8.5 mmol) is added slowly over 5 minutes. After 45 minutes add 0.2 equivalent of triethylamine. After 6 hours the reaction mixture was washed with brine (2×250 ml) and water (1×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue is recrystallized from N,N-dimethylformamide. The recrystallized material and the filtrate is stirred with methanol. The remaining solid precipitates is separated by filtration method, unite, and then dried in a drying apparatus of Abderhalden during the night with the receipt of 0.80 g of N-[4-(4-amino-2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in the form of a white solid, TPL 180,6-182,0°C. Analysis: calculated for C22H25N5O2S·0,25H2O: %C, 61,73; %N, 6,00; %N, 16,36.

Actually: %S, 61,79; %N, 6,04; %N, 16,43.

Example 2

N-[4-(4-Amino-2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide

Part a

tert-Butyl 4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)Buti is a carbamate (5,00 g, of 13.1 mmol) was mixed with hydrochloric acid (50 ml, 4.0 M in dioxane) and was shaken for 1.5 hours. The reaction mixture was diluted with dichloromethane (~200 ml). A saturated solution of sodium bicarbonate was added until reaching a pH of 8. In the aqueous phase was accompanied by the formation of sediment. The layers were separated. Sediment in the water layer was separated by means of filtration, stirred with water, and then separated by filtration method to obtain 3.6 g of 4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butane-1-amine.

Part b

The material from part a was combined with chloroform (600 ml) and warmed to 40°C. was Added triethylamine (3,48 ml, 25 mmol) and received the solution.

Added benzazolyl-chloride (1.60 ml, 12.5 mmol). This reaction mixture was shaken at 40°C during the night.

The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue is stirred in dichloromethane (~100 ml), washed with water (3×125 ml), dried over magnesium sulfate, and then concentrated under reduced pressure obtaining of 3.96 g of N-[4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in the form of a solid crystalline substance yellow, TPL 155,9-157,1°C.

The part With

3-Chloroperoxybenzoic acid (896 mg, 77% solution) was added during 5 minutes to a solution of N-[4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide (1.0 g, 2.4 mmol) in chloro who Orme (100 ml). After 2.5 hours, the added addition of 0.1 equivalent 3-chloroperoxybenzoic acid. After 3 hours the reaction mixture is kept at low temperature during the night. The reaction mixture was washed with saturated sodium bicarbonate solution (3×150 ml)and then concentrated under reduced pressure to obtain 1.44 g of crude product. This material was recrystallized from methyl acetate to obtain to 0.67 g of 1-{4-[(phenylsulfonyl)amino]butyl}-2-propyl-1H-imidazo-[4,5-C]quinoline-5N-oxide in a solid brown color, TPL 203,8-205,2°C.

Part D

Ammonium hydroxide (3.5 ml of a 27% solution) was added to a mixture of the material from part C and dichloromethane (15 ml). After 10 minutes slowly added taillored (0.35 g) for 5 minutes. After 45 minutes the reaction mixture was left at low temperatures for the weekend.

Added additional 35 mg of Teilhard and the reaction mixture was shaken for 1 hour. Separated the organic phase is then washed with a saturated solution of sodium bicarbonate (3×80 ml). In the aqueous phase was accompanied by the formation of sediment. This material was isolated by the method of filtration, and then recrystallized from methyl acetate. The obtained solid and filtrate were combined, dissolved in dichloromethane containing a small amount of methanol, and then purified by way of column chromatography (silica gel, n the wheel phase - 10% methanol in dichloromethane). The resulting material was purified by way of column chromatography (silica gel, mobile phase - 0-7,5% methanol in dichloromethane). This material was recrystallized 3 times from acetate to obtain 42 mg of N-[4-(4-amino-2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in the form of a white solid, TPL 158,8-160,8°C. Analysis: calculated for C23H27N5O2S-0.25 s3H6About2: %S, 62,15; %N, 6,22; %N, 15,59. Actually: %S, 62,41; %N, 5,91; %N, 15,41.

Example 3

N-[4-(4-Amino-2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide

Part a

Using the General method described in example 2, part a, tert-butyl 4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)BUTYLCARBAMATE (33,85 g) was subjected to hydrolysis with the receipt of 3.43 g of 4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)-butane-1-amine in the form of a whitish solid, TPL 172,2-174,2°C.

Part b

Using the General method described in example 2, part b, except that the reaction was carried out at room temperature, 4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)-butane-1-amine (1.20 g, 3.7 mmol) was reacted with benzazolyl-chloride (429 μl, 3.7 mmol) to obtain 0.75 g of N-[4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in a solid yellow color, TPL 137,0-138,1°C.

The part With

the use of the common way, described in example 2, part C, N-[4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide (0.95 g, 2.0 mmol) was oxidized with getting to 1.21 g of crude 1-{4-[(phenylsulfonyl)amino]butyl}-2-hexyl-1H-imidazo-[4,5-C]quinoline-5N-oxide.

Part D

Using the General method described in example 2, part D, the material from part C was minirovali to obtain 118 mg of N-[4-(4-amino-2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in the form of a whitish crystalline solid, TPL 84,8-85,4°C. Analysis: calculated for C26H33N5O2S·0,5H2O: %C, 63,91; %N, 7,01; %N, 14,33. Actually: %S, 63,63; %N, 6,93; %N, 14,80.

Example 4

N-[4-(4-Amino-2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide

Part a

Using the General method described in example 2, part b, except that the reaction was carried out at room temperature, 4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butane-1-amine (2.00 g, 7.1 mmol) was reacted with methanesulfonamide (1.65 ml of 21.3 mmol) to give 1.23 g of N-[4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in a solid yellow color, TPL 133,2-134,6°C.

Part b

Using the General method described in example 2, part C, N-[4-(2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide was oxidized to obtain 1.44 g of crude 1-{4-[(metals hanil)amino]butyl}-2-propyl-1H-imidazo-[4,5-C]quinoline-5N-oxide in a solid yellow color.

The part With

Using the General method described in example 2, part D, the material from part b was minirovali to obtain 0.21 g of N-[4-(4-amino-2-propyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a whitish crystalline solid, TPL 186,5-187,9°C. Analysis: calculated for C18H25N5C2S·0,25N2ABOUT: %S, 56,89; %N, 6,76; %N, 18,43. Actually: %S, 56,95; %N, 6,89; %N, 18,13.

Example 5

N-[4-(4-Amino-2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide

Part a

Using the General method described in example 2, part a, tert-butyl 4-(2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)BUTYLCARBAMATE (20,69 g) was subjected to hydrolysis with getting 14,94 g of 4-(2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butane-1-amine in the form of a whitish solid, TPL 84,8 to 88.7°C.

Part b

Using the General method described in example 2, part b, 4-(2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butane-1-amine (4,00 g, 14.9 mmol) was reacted with methanesulfonamide to obtain 1.78 g of N-[4-(2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in a solid yellow color.

The part With

Using the General method described in example 2, part C, the material from part b was oxidized with getting ~ 2,00 g of crude 1-{4-[(methylsulphonyl)amino]butyl}-2-ethyl-1H-imidazo-[4,5-C]quinoline-5N-oxide.

Part D

With COI is whether the common way, described in example 2, part D, the material from part C was treated with receipt of 0.42 g of N-[4-(4-amino-2-ethyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a white solid, TPL 203,3-204,4°C. Analysis: calculated for C17H23N5O2S: %C, 56,49; %N, 6,41; %N, 19,37. Actually: %C, 56,21; %N 6,36; %N, KZT 19.09.

Example 6

N-[4-(4-Amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide

Using the General method described in example 1, 1-(4-aminobutyl)-2-methyl-1H-imidazo-[4,5-C]-quinoline-4-amine (0.50 g, 1.9 mmol) was reacted with benzazolyl-chloride (to 0.24 ml, 1.9 mmol) with receipt of 0.38 g of N-[4-(4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide as brown granules, TPL 215,4-216,0°C. Analysis: calculated for C21H23N5O2S: %S, 61,59; %N, 5,66; %N, 17,10. Actually: %S, 61,24; %N, 5,65; %N, 16,95.

Example 7

N-[4-(4-Amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide

Using the General method described in example 1,1-(4-aminobutyl)-2-methyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1,00 g, 3.7 mmol) was reacted with methanesulfonamide ones (0.46 ml, 5.9 mmol) to obtain 0.16 g of N-[4-(4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a whitish solid, TPL 229,4-of 230.5°C. Analysis: calculated for C16H21N5O2/sub> S·0,25H2O: %C, 54,60; %N, 6,16; %N, 19,90. Actually: %C, 54,80; %N, 6,24; %N, 19,58.

Example 8

N-(4-Amino-2-butyl-1H-imidazo[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide

Part a

tert-Butyl 3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propylgallate (~80 g) was dissolved in 1,4-dioxane (400 ml) with gentle heating. Hydrochloric acid (55 ml of a 4.0 M solution in 1,4-dioxane) was added in one portion and the reaction mixture was heated to boiling.

The reaction was controlled by WPGH. Added an additional portion of the acid (150-200 ml)and the reaction mixture is boiled under reflux to complete the reaction. The reaction mixture was cooled to room temperature. The solid was isolated by filtration method of obtaining ~72 g of 3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)Propylamine hydrochloride. This material was combined with material from a previous experiment, and then was dissolved in water (400 ml).

The solution was neutralized by addition of solid potassium carbonate. At pH 7 fell at a solid residue. The precipitation was separated by filtration method, and then was dissolved in water (1500 ml). The pH was brought to pH 10 by addition of solid potassium carbonate. The solution was extracted with chloroform until such time as the analysis method WPGH showed that the water layer remained amines. The organic layers were combined, and then conc the Wali under reduced pressure to obtain 45 g of 3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)Propylamine.

Part b

The triethylamine (1.1 g, 10.6 mmol) was added under stirring to a solution of 3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)Propylamine (2.00 g, was 7.08 mmol) in dichloromethane (~150 ml). Added methanesulfonyl-chloride (892 mg, 7,79 mmol) and the reaction mixture was shaken in an atmosphere of nitrogen overnight. The reaction mixture was washed with 1% aqueous sodium bicarbonate solution (3×50 ml). The aqueous washings were extracted with dichloromethane (2×20 ml). The organic fractions were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 1.89 g of N-[3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide in the form of a light brown solid.

The part With

Using the General method described in example 2, part C, the material from part b was oxidized to obtain 1.24 g of N-[3-(2-butyl-5-oxido-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide.

Part D

Using the General method described in example 2, part D, the material from part C was treated with obtain 690 mg of N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide in the form of a light beige solid, TPL 239,2-240,8°C. Analysis: calculated for

C18H25O2S: %C, 57,58; %N, OF 6.71; %N, 18,65. Actually: %C, 57,37; %N, 6,78; %N, 18,42.

Example 9

N-[3-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]benzosulfimide

Part a

Using the General method described in example 8, part b, 3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)Propylamine (2.00 g, was 7.08 mmol) was reacted with benzazolyl-chloride (1,38 g, 7,79 mmol) to obtain 2.83 g of N-[3-(2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]benzosulfimide in the form of a light red foam.

Part b

Using the General method described in example 2, part C, the material from part a was oxidized to obtain 3.28 g of N-[3-(2-butyl-5-oxido-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]benzosulfimide.

The part With

Using the General method described in example 2, part D, the material from part b was treated with obtain 1.08 g of N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]benzosulfimide in the form of a light beige solid, TPL 210,5-212,0°C. Analysis: calculated for

C23H27N5O2S: %S, 63,13; %N, 6,22; %N, 16,01. Actually: %S, 62,89; %N, 6,16; %N, 15,74.

Example 10

N-[4-(4-Amino-2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)-butyl]methanesulfonamide

Part a

Using the General method described in example 1, 4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butane-1-amine (1,00 g, 3.1 mmol) was reacted with methanesulfonyl-chloride (0,48 ml, 6.2 mmol) with receipt of 1.15 g of N-[4-(2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a white solid.

Part b

The part With

Using the General method described in example 2, part D, the material from part b was treated with obtain 0.28 g of N-[4-(4-amino-2-hexyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a whitish solid, TPL 170,2-RUB 171.1°C. Analysis: calculated for

C21H31N5O2S: %S, 60,40; %N, OF 7.48; %N, 16,77. Actually: %S, 59,97; %N, 7,26; %N, 16,33.

Example 11

N-{8-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}benzosulfimide

Under nitrogen atmosphere a solution of 1-(8-aminoacetyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 ml) was cooled to 0°C. was Added triethylamine (415 μl, 2,98 mmol), and then benzazolyl-chloride (345 μl, a 2.71 mmol). The reaction mixture gave to slowly warm to room temperature, and then supported her during the night. The reaction mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by way of column chromatography (50 g of silica gel, mobile phase - 7.5% methanol in dichloromethane). Purified materialrequestlineitem from propyl, was ground into powder with hexane, and then dried in a vacuum heating Cabinet to obtain 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}benzosulfimide in the form of a yellow powder, TPL 146-149°C. Analysis: calculated for C27N35N5O3S: %S, 63,63; %N, 6,92; %N, 13,74. Actually: %S, 62,96; %N, 7,03; %N, To 13.09. By Karl-Fischer water content at the level of 0.16% or 0.045 mol.

1H NMR (300 MHz, DMSO-d6) δ 8,01 (d, J=7.8 Hz, 1H), 7,78 (m, 2H), 7,65-of 7.55 (m, 5H), was 7.45 (m, 1H), 7,28 (m, 1H), of 6.71 (s, 2H), 4,50 (m, 2H), 3,83 (m, 2H), 3,5 (broad s, 3H), 3,18 (m, 2H), 2,71 (m, 2H), 1.77 in (m, 2H), 1,38-1,17 (m, 10H).

13C NMR (75 MHz, DMSO-d6) δ 151,7, 151,3, 144,0, 141,0, 132,8, 132,6, 129,5, 127,0, 126,8, 125,9, 121,9, 120,4, 114,9, 70,5, 58,5, 45,3, 42,8, 30,0, 29,2, 28,8, 28,7, 27,5, 26,2, 26,1.

MC m/z 510 (M+H).

Example 12

N-{8-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}methanesulfonamide

Using the General method described in example 11, 1-(8-aminoacetyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (800 mg, 2,17 mmol) reacted with methanesulfonamide (172 μl, 2,17 mmol) to give 720 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}methanesulfonamide in the form of a yellow powder, TPL 109-110°C. Analysis: calculated for C22H33N5O3S: %S, 59,04; %N, 7,43; %N, 15,65. Actually: %S, 58,78; %N, 7,38; %N, 15,48.

1H NMR (300 MHz, DMSO-d6) δ 8,01 (d, J-8,3 Hz, 1H), 7.62mm (d, J=8,3 Hz, 1H), 7,42 (m, 1H), 7,26 (m, 1H), 6,91 (m, 1H), 6,51 (s, H), 4,51 (t, J=7,3 Hz, 2H), 3,83 (t, J=6,8 Hz, 2H), 3,34 (s, 3H), 3,18 (t, J=6,8 Hz, 2H), 2,89 (m, 2H), 2,86 (s, 3H), of 1.80 (m, 2H), 1.27mm (m, 10H).

13With NMR (125 MHz, DMSO-d6) δ 152,0, 151,0, 145,0, 132,6, 132,6, 126,7, 126,6, 121,56, 120,3, 115,1, 70,5, 58,5, 45,3, 42,8, 30,0, 29,7, 28,9, 28,8, 27,5, 26,4, 26,2. MC m/z 448 (M+1).

Example 13

N-[8-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]methanesulfonamide

Using the General method described in example 11, 1-(8-aminoacetyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1.2 g, 3,26 mmol) reacted with methanesulfonamide (260 μl, 3,26 mmol) to obtain 0,70 g of N-[8-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]methanesulfonamide in the form of a yellowish-brown powder, 121-124 TPL°C. Analysis: calculated for C23H35N5O3S: %S, 61,99; %N, 7,92; %N, 15,72. Actually: %S, 62,01; %N, 7,97; %N, Of 15.75.

1H NMR (300 MHz, DMSO-d6) δ 8,01 (d, J=8,3 Hz, 1H), to 7.61 (dd, J=8,3, 1.0 Hz, 1H), 7,41 (dt, J=8.3 and 1.5 Hz, 1H), 7,25 (dt, J=8,3, 1.5 Hz, 1H), 6,91 (t, J=4.9 Hz, 1H), 6,47 (s, 2H), 4,48 (t, J=7,3 Hz, 2H), 2,90 (m, 4H), of 2.86 (s, 3H), of 1.80 (m, 4H), of 1.44 (m, 6H), of 1.27 (m, 6H), is 0.96 (t, J=7,3 Hz, 3H).

13With NMR (500 MHz, DMSO-d6) δ 153,3, 152,1, 145,1, 132,5, 126,8, 126,7, 126,6, 121,5, 120,2, 115,2, 45,1, 42,8, 39,6, 30,1, 30,0, 29,8, 28,9, 28,8, 26,5, 26,4, 26,2, 22,3, 14,1.

MC m/z 446 (M+1).

Example 14

N-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide

In the atmosphere of nitrogen triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-buta is l-1H-imidazo-[4,5-C]-quinoline-4-amine (1.5 g, 5,04 mmol) in 1-methyl-2-pyrrolidone (75 ml). Was added a solution of 5-dimethylamino-1-naphthalenesulfonyl-chloride (1.5 g, 5,55 mmol) in 1-methyl-2-pyrrolidone. The reaction course was monitored according to WPGH, the reaction mixture was mixed with water (500 ml) and brought the pH to 10 by addition of solid potassium carbonate. The obtained yellow precipitate was isolated by the method of filtration, rinsed with water, and then purified by way of column chromatography (silica gel, mobile phase - 1-5% methanol in chloroform). The purified material was recrystallized from acetonitrile to obtain 1,76 g of N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamida in the form of solids, TPL 216,5-to 217.5°C. Analysis: calculated for C29H34N6O2S: %C, 65,64; %N, 6,46; %N, 15,84. Actually: %C, 65,52; %N, 6,44; %N, 15,90.

Example 15

N-[3-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)-propyl]4-methylbenzenesulfonamide

Using the General method described in example 14, 1-(3-aminopropyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1.5 g, 5,04 mmol) reacted with n-toluensulfonyl-chloride (1.08 g, 5,55 mmol) with receipt of 1.57 g of N-[3-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]-4-methylbenzenesulfonamide in the form of whitish powder, TPL 197,0-is 198.5°C. Analysis: calculated for C24H29N5O2S: %C, 63,83; %N, 6,47; %N, 15,51. Actually: %C, 63,68; %N, 6,40;%N, 15,51.

Example 16

N-{3-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-3-yl]propyl}methanesulfonamide

Using the General method described in example 11,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1,53 g, 5,11 mmol) reacted with methanesulfonamide to obtain 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide in the form of light yellow needle-like crystals TPL 193-194°C. Analysis: calculated for C17H23N5O3S: %C, 54,09; %N, 6,14; %N, 18,55. Actually: %S, 54,09; %N, 5,93; %N, Be 18.49.

Example 17

N-[8-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]benzosulfimide

Using the General method described in example 11, the reaction of 1-(8-aminoacetyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1.0 g, of 2.72 mmol) with benzazolyl-chloride (350 μl, of 2.72 mmol) and got to 1.38 g of N-[8-(4-amino-2-butyl-1H-imidazo-[4,5-c]quinoline-1-yl)octyl]benzosulfimide in the form of a whitish powder, TPL 143-144°C. Analysis: calculated for C28H37N5O2S: %C, 66,24; %N, 7,35; %N, 13,79. Actually: %C, 66,08; %N, 7,25; %N, 13,72. Titration according to Karl Fischer showed the water content of 0.23%.

1H NMR (300 MHz, DMSO-d6) δ 7,98 (d, J=7.8 Hz, 1H), to 7.77 (m, 2H), 7,62-7,53 (m, 5H), 7,41 (m, 1H), 7,25 (m, 1H), 6,47 (s, 2H), 4,47 (m, 2H), 2,90 (m, 2H), 2,70 (q, J=6.3 Hz, 2H), 1,78 (m, 4H), 1,49-1,17 (m, 12H), of 0.95 (t, J=7,3, 3H).

13C NMR (125 MHz, DMSO-d6) δ 153,3, 152,0, 145,0, 141,0, 132,5, 129,5, 126,82, 126,76, 126,7, 126,6, 121,5, 120,3, 120,2, 115,1, 45,1, 42,8, 30,0, 29,2, 28,8, 28,7, 26,5, 26,2, 26,1, 22,3, 14,2, 14,1.

MC m/z 507 (M+1).

Example 18

N-{3-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl} benzosulfimide

Using the General method described in example 11, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1,53 g, 5,11 mmol) reacted with benzazolyl-chloride (993 mg, 5,62 mmol) with receipt of 1.37 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}benzosulfimide in the form of a white powder, TPL 149-151°C. Analysis: calculated for C22H25N5O3S: %S, 60,12; %N, 5,73; %N, 15,93. Actually: %S, 60,40; %N, Of 5.82; %N, 15,85.

Example 19

N-[4-(4-Amino-2-pentyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide

Using the General method described in example 14, 1-(4-aminobutyl)-2-pentyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1.50 g, 4.6 mmol) was reacted with methanesulfonamide (or 0.57 ml, 7.4 mmol) to obtain the 636 mg of N-[4-(4-amino-2-pentyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a whitish solid, TPL 136,8-138,1°C. Analysis: calculated for C20H29N5O2S: %C, 59,53; %N, 7,24; %N, OF 17.35. Actually: %C, 59,50; %N, 7,31; %N, Ls 16.80.

Example 20

N-[4-(4-Amino-2-pentyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]Ben is alcolholic

Using the General method described in example 1, 1-(4-aminobutyl)-2-pentyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1,00 g, 3.1 mmol) was reacted with benzazolyl-chloride (0.51 ml, 4.0 mmol) to give 0.35 g of N-[4-(4-amino-2-pentyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]benzosulfimide in the form of a yellow crystalline solid. Analysis: calculated for C25H31N5O2S·0,5H2O: %C, 63,27; %N, 6,80; %N, OF 14.76. Actually: %S, 62,99; %N, 6,61; %N, 14,42.

Example 21

N-[8-(4-Amino-1H-imidazo-[4,5-C]-quinoline-1-yl)octyl]methanesulfonamide

Using the General method described in example 11, 1-(8-aminoethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (of 3.85 mmol) reacted with methanesulfonamide (310 μl, of 3.85 mmol) with receipt of 0.43 g of N-{8-[4-amino-1H-imidazo-[4,5-C]-quinoline-1-yl]octyl}methanesulfonamide in the form of a whitish powder, TPL 153 to 155°C. Analysis: calculated for C19H27N5O2S: %C, 58,59; %N, 6,99; %N, 17,98; %S, 8,23. Actually: %C, 58,40; %N, 6,99; %N, 17,71; %S, 8,14.

1H NMR (300 MHz, DMSO-d6) δ to 8.20 (s, 1H), 8,03 (d, J=7.8 Hz, 1H), 7,63 (d, J=8,3 Hz, 1H), 7,45 (m, 1H), 7,27 (m, 1H), 6,91 (m, 1H), 6,63 (d, 2H), 4,59 (m, 2H), 2,89 (m, 2H), 2,86 (s, 3H), of 1.86 (m, 2H), 1.41 to 1,25 (m, 10H).

13With NMR (125 MHz, DMSO-d6) δ 152,5, 145,2, 143,2, 132,0, 128,5, 127,1, 126,5, 121,6, 120,8, 115,2, 46,9, 42,8, 39,6, 30,0, 29,7, 28,81, 28,78, 26,4, 26,1.

MC m/z 390 (M+1).

Example 22

N-{3-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-hee is Olin-1-yl]propyl}-4-methylbenzenesulfonamide

Using the General method described in example 11, the reaction between 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1,53 g, 5,11 mmol) and n-toluensulfonyl-chloride (1.07 g, 5,62 mmol) to give 750 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}-4-methylbenzenesulfonamide in the form of solids, TPL 189-191°C. Analysis: calculated for C23H27N5O3S·0,50H2O: %C, 59,72; %N, 6,10; %N, 15,14. Actually: %S, 59,73; %N, 5,95; %N, 15,08.

Example 23

N-[4-(4-Amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide

A solution of 1-(4-aminobutyl)-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine (1.50 g, 3.7 mmol) in chloroform (150 ml) was cooled in an acetone/ice bath, then slowly added methanesulfonyl anhydride (0,79 g, 3.7 mmol). After 1.75 hours added 0,018 g of the anhydride. 2.5 hours was added 0,079 g of the anhydride. After 3 hours the reaction mixture was washed with 1% aqueous sodium carbonate solution (3×150 ml). The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 2.2 g of a light yellow precipitate. The residue was combined with 1% aqueous sodium carbonate solution (200 ml) and brought the pH up to 13 by addition of solid sodium carbonate and 50% sodium hydroxide. Separated organicheskuyu, washed with 1% aqueous sodium carbonate solution (3×200 ml), dried over magnesium sulfate, and then concentrated under reduced pressure to get to 2.18 g of brown residue. This material was mixed with acetate. The obtained solid substance was separated by receipt of 1.25 g of N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide in the form of a white solid, TPL 167,0-167,8°C. Analysis: calculated for C20H33N5O2S: %C, 58,94; %N, 8,16; %N, 17,18. Actually: %C, 58,79; %N, 7,92; %N, 17,02.

Example 24

N-{3-[4-Amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide

A mixture of 1-(3-aminopropyl)-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (2.0 g, 6.7 mmol), triethylamine (1.5 ml, 15 mmol) and acetonitrile (75 ml) was heated to obtain a solution. Methanesulfonyl anhydride (1.28 g, 7.4 mmol) was added in one portion. After 5 minutes was added a small amount of anhydride. The reaction mixture was left on a shaker overnight. The reaction mixture was rapidly diluted in 1% aqueous solution of sodium carbonate. The aqueous layer was extracted with chloroform. The organic fraction was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was dried in high vacuum for 3 hours and got 2,73 g of a glassy solid. E is from the material was recrystallized from methanol and got to 1.38 g of N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide, TPL 208,2-209,6°C.

Analysis: calculated for C17H23N5O3S: %C, 54,09; %N, 6,14; %N, 18,55.

Actually: %C, 53,97; %N, 6,29; %N, 18,32.

Example 25

N-(3-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-2,2-dimethylpropyl}methanesulfonamide

Using the General method described in example 11, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (0,22 g, 0,672 mmol) reacted with methanesulfonamide (125 μl) to obtain 270 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-2,2-dimethylpropyl}methanesulfonamide in the form of a cream-colored powder, TPL 204,0-206,0°C. Analysis: calculated for C19H27N5O3S·0,50N2O: %C, 55,05; %N, FOR 6.81; %N, 16,89; %S, 7,74. Actually: %C, 55,10; %N, 6,58; %N, 17,23; %S, 7,51. % H2About: 2,17. In fact: 2,28 (Karl-Fischer).

1H NMR (300 MHz, DMSO-d6) δ at 8.36 (d, J=8,3 Hz, 1H), to 7.59 (d, J=8,3 Hz, 1H), 7,38 (m, 2H), 7,20 (m, 1H), of 6.49 (s, 2H), to 4.81 (br s, 1H), 4,39 (br s, 1H), 3,82 (m, 2H), 3.27 to (s, 3H), 3,19 (br s, 2H), to 3.02 (d, J=6,8 Hz, 2H), 2,94 (s, 3H), of 0.82 (br s, 6H).

13With NMR (125 MHz, DMSO-d6) δ 152,5, 152,0, 145,3, 133,9, 126,8, 126,7, 126,6, 121,5, 120,7, 115,8, 71,0, 58,5, 51,8, 51,5, 39,7, 39,0, 28,3, 24,4, 23,1. MC m/z 406 (M+H).

Example 26

N-{3-[4-Amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide

Using the General method described in example 14, except that as the e of the solvent used chloroform, carried out the reaction between 1-(3-aminopropyl)-2-(methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1,53 g, 5,11 mmol) and 5-dimethylamino-1-naphthalenesulfonyl-chloride (by 5.87 mmol) to give 1.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamida in the form of a yellow solid, TPL 210-215°C. Analysis: calculated for C28H32N6O3S·1,50N2ABOUT: %S, 60,09; %N, 6,30; %N, 15,02. Actually: %S, 59,89; %N, 6,22; %N, 14,86.

Example 27

N-[3-(4-Amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide

Using the General method described in example 24, the reaction between 1-(3-aminopropyl)-2-methyl-1H-imidazo-[4,5-C]-quinoline-4-amine (2.0 g, 7.8 mmol) and methanesulfonyl anhydride (1,49 g, 8.6 mmol) to obtain 1.2 g of N-[3-(4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)propyl]methanesulfonamide in the form of solids, TPL 236,0-238,0°C. Analysis: calculated for C15H19N5O2S·0,25H2O: %C, 53,32; %N, OF 5.82; %N, 20,72. Actually: %S, 53,35; %N, 5,72; %N, 20,57.

Example 28

N-{3-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide

Using the General method described in example 24, the reaction between 1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine (2.0 g, 66 mmol) and methanesulfonyl anhydride (1.26 g, 7,3 mmol) to give 630 mg of N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide in the form of solids, TPL 150,0-to 152.0°C. Analysis: calculated for C17H27N5O3S: %S, 53,52; %N, 7,13; %N, 18,36. Actually: %S, 53,27; %N, 7,12; %N, 18,37.

Example 29

N-{3-[4-Amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide

Using the General method described in example 24, except that chloroform was used instead of acetonitrile, the reaction between 1-(3-aminopropyl)-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine (2.6 g, 8,35 mmol) and methanesulfonyl anhydride (3+ g) to give 850 mg of N-{3-[4-amino-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide in the form of solids, TPL 212,0-214,0°C. Analysis: calculated for C17H27N5O3S: %S, 53,52; %N, 7,13; %N, 18,36. Actually: %S, 53,25; %N, 7,16; %N, 18,09.

Example 30

N-{3-[4-Amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl}methanesulfonamide

Using the General method described in example 11, except that chloroform was used instead of dichloromethane, the reaction between 1-(3-aminopropyl)-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-4-amine (2.00 g, 5,32 mmol who) and methanesulfonamide (3+ g) obtaining of 1.38 g of N-{3-[4-amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl]propyl)methanesulfonamide in the form of solids, TPL 176-178°C. Analysis: calculated for C23H27N5O3S: %S, 60,93; %N, 6,00; %N, 15,44. Actually: %S, 60,71; %N, 5,98; %N, 15,45.

Example 31

N-{4-[4-Amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl]butyl}methanesulfonamide

Using the General method described in example 24, except that instead of acetonitrile used pyridine, the reaction between 1-(3-aminobutyl)-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-4-amine (2.00 g, 5.1 mmol) and excess methanesulfonamido anhydride with the receipt of 1.36 g of N-{4-[4-amino-2-(3-phenoxypropan)-1H-imidazo-[4,5-C]-quinoline-1-yl]butyl}methanesulfonamide in the form of solids, TPL 156,4-157,1°C. Analysis: calculated for C24H29N5O3S: %S, 60,48; %N, 6,34; %N, 14,69. Actually: %S, 60,75; %N, 6,36; %N, 14,31.

Example 32

N-[4-(4-Amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide hydrochloride

Using the General method described in example 23, the reaction between 1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-4-amine (1,00 g, 3.7 mmol) and methanesulfonyl anhydride (0.96 g, 5.5 mmol) in the presence of triethylamine (from 0.76 ml, 5.5 mmol) to give 0.55 g of the free base of the desired product. This material was combined with methanol (~20 ml), stirred, allowed to cool to room temp the atmospheric temperature, and then was filtered to remove a small amount of insoluble material. The volume of the filtrate was reduced to ~10 ml and then mixed with 1 N. hydrochloric acid (3 ml). Added diethyl ether (15 ml), and then the mixture was concentrated under reduced pressure. The obtained residue was mixed with isopropyl alcohol to obtain a white solid, which was isolated by filtration method, and then dried and received and 0.46 g of N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]methanesulfonamide-hydrochloride, TPL >250°C. Analysis: calculated for C16H25N5O2S·1.00 m HCl·1,00 H2O: %C, 47,34; %N, 6,95; %N, 17,25. Actually: %S, 47,40; %N, Of 6.49; %N, 17,22.

Example 33

N-[2-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)ethyl]-4-methylbenzenesulfonamide

To a cooled (0°C.) solution of 1-(2-amino-ethyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (3.0 g, 10.6 mmol) in 1-methyl-2-pyrrolidone (100 ml) was added triethylamine (1.1 g, 15.9 mmol). The solution taillored (2,11 g, 11.1 mmol) in 1-methyl-2-pyrrolidone (20 ml) was added slowly, dropwise. The reaction mixture was allowed to warm to room temperature, and this temperature was maintained throughout the night. The reaction mixture was poured into water (1500 ml) and brought the pH to 9. A white precipitate was separated by means of filtration, and then recrystallized from acetonitrile (60 ml) to obtain the of 3.9 g of N-[2-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)ethyl]-4-methylbenzenesulfonamide, TPL 187,0-188,0°C. Analysis: calculated for C23H27N5O2S·0,3H2ABOUT: %S, 62,29; %N, 6,28; %N, 15,79. Actually: %S, Totals 62.52; %N, 6,36; %N, 15,88.

Example 34

N-[2-(4-Amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)ethyl]methanesulfonamide

Methanesulfonanilide (1.27 g, 11.1 mmol) was slowly added to a solution of 1-(2-amino-ethyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (3.0 g, 10.6 mmol) in pyridine (60 ml). The reaction mixture was stirred at room temperature overnight, and then concentrated to dryness. The residue was combined with warm dichloromethane and water, and then filtered with the formation of a whitish solid. Declaratively layer was concentrated with the formation of a whitish solid. Both solids were combined, and then recrystallized from N,N-dimethylformamide to obtain 1.1 g of N-[2-(4-amino-2-butyl-1H-imidazo-[4,5-C]-quinoline-1-yl)ethyl]methanesulfonamide in the form of a white solid, TPL 210,0-211,0°C. Analysis: calculated for C17H23N5O2S: %C, 56,49; %N, 6,41; %N, 19,37. Actually: %C, 56,45; %N, Of 6.49; %N, 19,50.

Example 35

1-[4-(1,1-Dioxothiazolidine-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine

In nitrogen atmosphere was dissolved 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (500 mg, 1.6 mmol) in dichloromethane (5 ml) and triethylamine (0.33 m is, 2.4 mmol). Was added dropwise 3-chloropropanesulfonyl-chloride (to 0.19 ml, 1.6 mmol) and the reaction mixture was shaken for 2 hours. The solvent was removed in vacuum. The residue was dissolved in N,N-dimethylformamide (5 ml) was added 1,8-diazabicyclo-[5,4,0]-undec-7-ene (of 0.48 ml, 3.2 mmol). The reaction mixture was shaken for 72 hours, and then poured into water and was extracted with dichloromethane. The organic layer was washed with water and then with brine; dried (Na2SO4); decantation and evaporated to obtain the crude product as a brown oil. Purification was performed by the method of pulsed column chromatography (silica gel, gradient elution methanol/dichloromethane 100:0 to 94:6) followed by recrystallization from acetonitrile to obtain 289 mg of 1-[4-(1,1-dioxothiazolidine-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine as a yellow crystalline solid, TPL 156,4-157,7°C.

1H-NMR (500 MHz, DMSO-d6) δ 8,04 (a, J=7,4 Hz, 1H), 7.62mm (dd, J=8,3,1,2 Hz, 1H); 7,42 (ddd, J=8,2, 7,0, 1.2 Hz, 1H), 7,26 (ddd, J=8,2, 7,0, 1.2 Hz, 1H), 6.48 in (bs, 2H), 4,54 (t, J=7,6 Hz, 2H), 3,84 (t, J=6,7 Hz, 2H), 3,29 (s, 3H), 3,22-3,12 (m, 6H), of 2.93 (t, J=6.6 Hz, 2H), 2,23 and 2.13 (m, 2H), 1,90-of 1.65 (m,4H).

13C-NMR (125 MHz, DMSO-d6) δ 151,6, 150,6, 144,8, 132,2, 126,5, 126,3, 121,2, 120,0, 114,7, 70,2, 58,1, 46,5, 46,1, 44,5, 43,6, 27,1, 24,1, 18,3.

Analysis: calculated for C20H27N5O3S: %S, 57,53; %N, 6,52; %N, 16,77; %S OF 7.68. Actually: %S, 57,52; %N, 6,67; %N, 16.88 In; %S, 7,71

Example 36

2-Butyl-1-[4-(1,1-dioxothiazolidine-2-yl)butyl]-1H-imidazo-[4,5-C]-quinoline-4-amine

Using the General method described in example 35, except that instead of dichloromethane used 1-methyl-2-pyrrolidone, carried out the reaction between 1-(4-aminobutyl)-2-butyl-1H-imidazo-[4,5-C]-quinoline-4-amine (5.0 g, 16.0 mmol) and 3-chloropropanesulfonyl (2.83 g, 16.0 mmol) to obtain 0.75 g of 2-butyl-1-[4-(1,1-dioxothiazolidine-2-yl)butyl]-1H-imidazo-[4,5-C]-quinoline-4-amine as a white solid, TPL 173, 0mm-176,0°C.

1H-NMR (300 MHz, DMSO-d6) δ 8,30 (d, J=8,1 Hz, 1H), 7.62mm (d, J=8,2 Hz, 1H), 7,41 (t, J=7,6 Hz, 1H), 7,26 (t, J=8.0 Hz, 1H), 6.48 in (bs, 2H), 4,51 (t, J=7.5 Hz, 2H), 3,18-3,11 (m, 4H), 2,96-2,89 (m, 4H), 2,22-2,12 (m, 2H), 1,92-1,63 (m, 6N), a 1.45 (sextet, J=7.4 Hz, 2H), of 0.96 (t, J=7,3 Hz, 3H).

13C-NMR (75 MHz, DMSO-d6) δ 153,0, 151,7, 144,7, 132,2, 126,4, 126,2, 121,1, 120,0, 114,7, 46,5, 46,1, 44,3, 43,6, 29,7, 27,1, 26,1, 24,1, 22,0, 18,3, 13,8. MC (CI) m/e 416,2124 (416,2120 calculation for C21H30N5O2S, M+H). Analysis: calculated for C21H29N5O2S: %C, 60,70; %N, 7,03; %N, 16,85; %S, 7,72. Actually: %C, 60,67; %N, 6,94; %N, 17,02; %S, 7,42.

Example 37

N-{2-[4-Amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylethyl}methanesulfonamide

Part a

Well mixed solution of 4-chloro-3-nitroquinoline (17.3 g, or 83.2 mmol) in 200 ml anhydrous CH2Cl2in the atmosphere of N2the process is tivali by triethylamine (23,2 ml, 166,4 mmol) and 1,2-diamino-2-methylpropanol (to 9.57 ml, of 91.5 mmol). After shaking overnight, the reaction mixture was diluted, Prilepa 800 ml of CHCl3, washed with water (3×300 ml) and brine (300 ml). The organic fraction was dried over Na2SO4and concentrated to obtain 2-methyl-N1-(3-nitroanilin-4-yl)propane-1,2-diamine (21,0 g) as a bright yellow solid.

Part b

A solution of 2-methyl-N1-(3-nitroanilin-4-yl)propane-1,2-diamine (2,60 g, 10.0 mmol) in 50 ml of THF, under nitrogen atmosphere, was cooled to 0°and treated With 10 ml of 1 n NaOH solution. Then to vigorously perelyaeva the solution was added di-tert-BUTYLCARBAMATE (2,18 g, 10.0 mmol).

Then the reaction mixture was left to warm to room temperature and was stirred up during the night. Added additional portion 400 mg di-tert-BUTYLCARBAMATE and shaking was continued for 3 days. The reaction mixture was then treated with ethyl acetate (200 ml) and washed with water (2X) and brine. The organic fraction was dried over Na2SO4and concentrated to obtain a yellow solid, which was treated with a 10% mixture of ethyl acetate/hexane. The solid was isolated by the method of filtration and was dried in vacuum overnight to obtain tert-butyl-1,1-dimethyl-2-[(3-nitroanilin-4-yl)amino]ethylcarbamate (2,80 g) as a yellow powder.

The part With

A solution of tert-butyl-1,1-dimethyl-2-[(3-nitroanilin-4-yl)amino]ethylcarbamate (3.50 g, 9,72 mmol) in 150 ml of toluene was treated with 0.3 g of 5% Pt on carbon was shaken in an atmosphere of H2(3 ATM, 3 kg/cm2within 6 hours. The solution is then filtered through a layer of celite and concentrated to obtain totaling 3.04 g of crude tert-butyl 2-[(3-aminoquinoline-4-yl]-1,1-dimethylthiocarbamate in the form of a light orange foam-like substance.

Part D

A solution of tert-butyl 2-[(3-aminoquinoline-4-yl]-1,1-dimethylthiocarbamate (totaling 3.04 g of 9.21 mmol) in 50 ml of CH2Cl2was cooled to 0°C and treated with triethylamine (1,41 ml, 10,13 mmol) and ethoxyacetylene (of 1.02 ml, 10,17 mmol). After 2 hours the reaction mixture was concentrated under reduced pressure. The resulting syrup was transferred into 100 ml of ethanol and treated with 4.5 ml of triethylamine. The solution was heated under reflux overnight. The reaction mixture was concentrated, transferred in 100 ml of CH2Cl2and washed with water (2X) and brine. The organic fraction was dried over Na2SO4and concentrated. The resulting syrup was purified by way of column chromatography (SiO2, 80% ethyl acetate/hexane) to obtain tert-butyl-2-[2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (of 1.57 g) as a foam peach color.

Part E.

A solution of tert-butyl 2-[2-(etoksilat the l)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (1,57 g, of 3.94 mmol) in 30 ml of CH2Cl2processed 3-chloroperoxybenzoic acid (77%, 1.01 g, of 4.57 mmol). After shaking for 2 hours, the reaction mixture was treated with 30 ml of additional CH2Cl2and washed with a 1% solution of Na2CO3(2×30 ml), N2O and brine. The organic fraction was then dried over Na2SO4and concentrated to obtain tert-butyl-2-[2-(2-(ethoxymethyl)-5-oxido-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (1,58 g) as a light brown foam.

Part F

A solution of tert-butyl 2-[2-(2-(ethoxymethyl)-5-oxido-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (1,57 g, with 3.79 mmol) in 20 ml of 1,2-dichloroethane was heated to 70°C. and was treated with 2 ml of concentrated solution of NH4OH. To the vigorously stirred solution was added solid n-toluensulfonyl-chloride (795 mg, of 4.17 mmol). Then the reaction mixture is hermetically closed in a pressure vessel and heating was continued for 2 hours. The reaction mixture is then cooled and treated with 50 ml of CHCl3. Then the reaction mixture was washed with water, 1% solution of Na2CO3(3X) and brine. The organic fraction was dried over Na2SO4and concentrated to obtain the product as a light brown oily liquid. The obtained liquid was purified by way of column chromatography (Si 2, 2-5% Meon/CHCl3) to obtain tert-butyl-2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (1.26 g) as a pale yellow foamy substance.

Part G

tert-Butyl 2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylthiocarbamate (1.26 g, of 3.05 mmol) was dissolved in 10 ml of ethanol and was treated with 10 ml of 2 M HCl in ethanol. After heating under reflux for 2 hours the reaction mixture was cooled and concentrated under reduced pressure. The obtained yellow solid was dissolved in 50 ml

H2O and was extracted with CHCl3(20 ml). The organic layer is discarded and the aqueous fraction was podlachian (pH~12) adding a concentrated solution of NH4OH. Then there was the extraction CHCl3(4×20 ml) and the combined organic fractions were dried with Na2SO4and concentrated to obtain 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (808 mg) as a pale brown powder, TPL 161,0-162,0°C. MS m/z 314 (M+H).

1H NMR (300 MHz, d6-DMSO) δ 8,30 (d, J=7.7 Hz, 1H), to 7.59 (dd, J=1,2, 8,3 Hz, 1H), 7,40 (ddd, J=1,0, 7,2, 8,1 Hz, 1H), 7,21 (ddd, J=1,2, 7,0, 8,2 Hz, 1H), to 6.57 (s, 2H), 4,94 (br s, 2H), br4.61 (br s, 2H), 3,52 (q, J=7,0 Hz, 2H), 1,61 (s, 2H), 1,31 (t, J=7.0 Hz, 3H), of 1.07 (s, 6H).

13With NMR (75 MHz, d6-DMSO) δ 152,4, 151,1, 145,7, 134,3, 126,8, 126,7, 121,7, 120,8, 115,7, 65,6, 65,2, 55,8, 52,5, 29,2, 15,4.

Analysis: calculated for C H23N5O: %C, 65,15; %N, 7,40; %N, TO 22.35.

Actually: %C, 65,04; %N, 7,52; %N, 22,07.

Part N

1-(2-Amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (111 mg, 0,355 mmol) was dissolved in 5 ml anhydrous CH2Cl2and was cooled to 0°C. in a nitrogen atmosphere. To the stirred solution was added Et3N (99 μl, 0.71 mmol) and methanesulfonyl-chloride (28 μl, 0.36 mmol) and the reaction mixture was allowed to warm to room temperature over night. The reaction was then stopped by adding a saturated solution of NaHCO3(5 ml). The organic layer was separated and washed with water (2×5 ml) and brine, dried over Na2SO4and concentrated under reduced pressure to get foamy substance beige-brown color. After purification by way of column chromatography (SiO2and 2.5%-5% Meon/CHCl3) was obtained N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylethyl}methanesulfonamide (75 mg) as a white foamy substance,

TPL 105,0-110,0°C. MS m/z 392 (M+N)+.

1H NMR (300 MHz, CDCl3) δ of 8.06 (dd, J=1,0, 8,3 Hz, 1H), 7,79 (dd, J=1,1, 8,4 Hz, 1H), 7,51 (ddd, J=1,3, 7,0, and 8.4 Hz, 1H), 7,31 (ddd, J=1,3, 7,0, 8,3 Hz, 1H), 5,90 (br s, 1H), 5,51 (br s, 2H), 4,96 (s, 2H), 4.92 in (br s, 2H), 3,74 (q, J=7,0 Hz, 2H), to 3.02 (s, 3H), of 1.55 (br s, 6H), of 1.29 (t, J=7.0 Hz, 3H).

13With NMR (75 MHz, CDCl3) δ 152,0, 150,8, 145,5, 135,2, 127,8, 127,6, 127,2, 122,2, 120,6, 116,0, 67,2, 65,4, 58,4, 55,8, 45,3, 26,6, 15,3.

Analysis: calculated for C18K25 N5O3S·0,75H2O: C, 53,38; %N, 6,60; %N, 17,29.

Actually: %S, 53,49; %N, 6,23; %N, 16,93.

Example 38

N-[4-(4-Amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]econsultant

Using the General method described in example 1, the reaction between 1-(4-aminobutyl)-2-methyl-1H-imidazo-[4,5-C]-quinoline-4-amine (1,00 g, 3.7 mmol) and econsultancy-chloride (2,11 ml of 22.3 mmol) to give 85 mg of N-[4-(4-amino-2-methyl-1H-imidazo-[4,5-C]-quinoline-1-yl)butyl]acanalonia in the form of a whitish solid, TPL 210,7-211,6°C.

Example 39

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

Using the General method described in example 38, part b, except that chloroform was used instead of dichloromethane, the reaction between 1-(4-aminobutyl)-2-(cyclopropylmethyl)-1H-imidazo-[4,5-C]-quinoline-4-amine (1,00 g, 3.2 mmol) and methanesulfonyl anhydride (1.29 g, 7.4 mmol) to obtain the 0,42 g of N-{4-[4-amino-2-(cyclopropylmethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]butyl}methanesulfonamide in a solid brown color, TPL 199,7-200,7°C.

INDUCTION of CYTOKINES IN HUMAN CELLS

The system of human blood cells in vitro was used to assess the induction of cytokines substances presented in this invention. The evaluation of this active the ti is based on the measurement of the amount of interferon and factor (α), tumor necrosis (IFN and TNF, respectively), secreted into the culture medium, as described by Testerman et. al. "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Preparation of blood cells for culturing

Whole blood collected from a vein in healthy donors in a test tube "vacutainer" EDTA. Mononuclear cells from peripheral blood (ocpc) were isolated from whole blood by centrifugation in a density gradient using Histopaque®-1077 (Sigma Chemicals, St. Louis, Missouri, USA). Selected OKC suspended in 3-4×106cells/ml in RPMI medium 1640 containing 10% fetal serum bull, 2 mm L-glutamine and 1% solution of penicillin/streptomycin (complete RPMI). Suspension OKC was added in sterile die for cultivation with 48 cells with a flat bottom (Costar, glenbridge, Maryland, or Becton Dickinson Labware, Lincoln city Park, new Jersey, USA)containing an equal volume of complete RPMI medium containing the test substance.

Preparation of matter

Connection solubilizer in dimethyl sulfoxide (DMSO). The concentration of DMSO should not exceed a final concentration of 1% to be added to the cells for cultivation.

Incubation

The solution of the test substance was added at 60 μm in the first cell containing complete RPMI medium, and pursue consistent (three-fold or ten-fold) dilution. Then the cells were added to equal volumes of WM is ansii OKC, creating the desired range of concentrations of the test substance. The final concentration of the suspension OKC is 1.5-2×106cells/ml. Die cover with a sterile plastic lids, gently mixed, and then incubated for 18 to 24 hours at 37°C in an atmosphere of 5% carbon monoxide.

Division

After incubation, the plates centrifuged for 5-10 minutes at 1000 rpm (~200 × g) at 4°C. the Supernatant of the cell culture is harvested by means of a pipette with a sterile polypropylene tip and transferred to sterile polypropylene tubes. Samples stored at a temperature of from -30 to -70°C until analysis. Samples analyzed for interferon (α) and factor-α tumor necrosis immunoenzymatic ELISA method.

Interferon-α and factor-α tumor necrosis analysis method ELISA

The concentration of interferon (a) is determined by the ELISA method using a set of Human Multi-Species from PBL Biomedical Laboratories, new-Brunswick, new Jersey, USA.

The concentration of factor-α tumor necrosis (TNF) is determined using ELISA kits manufactured by Genzyme, glenbridge, Maryland, USA; R&D Systems, Minneapolis, Minnesota, or Pharmingen, San Diego, California, USA.

The following table presents a list of minimum concentrations of each substance, which, according to test results, capable inducion the TB interferon and minimum concentrations of each substance, which, according to test results, is able to induce tumor necrosis factor. Icon ** indicates that is not marked induction nor at any of the tested concentrations(0,12, 0,37, 1,11, 3,33, 10 and 30 Microm). Icon *** indicates not detected induction nor in any of the studied concentrations (0.0001, 0,001, 0,01, 0,1,1 and 10 Microm).

1,11
Induction of cytokines in human cells
RoomThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
10,121,11
20,371,11
31,111,11
40,041,11
50,010,12
60,370,04
7 0,040,37
80,011,11
90,373,33
100,121,11
110,010,01
120,010,01
130,010,01
143,33**
151,113,33
160,010,01
170,120,01
180,011,11
190,010,12
200,1210
210,37
220,040,12
230,011,11
240,123,33
250,010,04
261,113,33
270,3710
280,0110
290,010,37
30**10
31**10
320,12**
331,111,11
340,010,04
360,010,12
370,040,12

The present invention is described with reference to some examples and options for implementation. The foregoing detailed description and examples are presented only to clarify understanding and does not imply any optional constraints. As obviously experienced professionals, many changes may be made to the described examples without violating the scope and essence of the present invention. Thus, the scope of the invention should not be limited to the exact details described herein compositions and structures, but rather the language of the claims presented below.

1. N-{2-[4-Amino-2-(ethoxymethyl)-1H-imidazo-[4,5-C]-quinoline-1-yl]-1,1-dimethylethyl}methanesulfonamide or pharmaceutically acceptable salt of this substance.

2. Pharmaceutical composition having the ability to induce the biosynthesis of cytokines containing a therapeutically effective amount of a substance or its salt according to claim 1 and a pharmaceutically acceptable carrier.

3. Method of induction of the biosynthesis of cytokines in the body of an animal, comprising introducing an effective amount of a substance or its salt according to claim 1 in the body of the animal.

4. A method of treating a viral disease in an animal, comprising introducing an effective amount of a substance or its salt according to claim 1 into the body W is animal.

5. A method of treating cancer in an animal, comprising introducing an effective amount of a substance or its salt according to claim 1 in the body of the animal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to 5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine or to its salt, as well as a pharmaceutical composition which inhibits secretion of gastric acid based on the said compound. Description is given of production of the new compound and a pharmaceutical composition based on the new compound, which can be used in medicine for treating such diseases as gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal reflux, Zollinger-Ellison syndrome, symptomatic gastroesophageal reflux, endoscopy negative gastroesophageal reflux, gastroesophageal regurgitation, pharyngolaryngeal paresthesia, Barrett's esophagus, Non-steroidal anti-inflammatory drug (NSAID) induced ulcer, gastritis, gastric hemorrhage, gastrointestinal hemorrhage, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperchlorhydria, dyspepsia, gastroparesis, senile ulcer, intractable ulcer, heartburn, bruxism, stomach ache, heavy stomach or erosive gastritis.

EFFECT: increased effectiveness of composition and disease treatment.

7 cl, 6 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of formula (I) , where A is optionally substituted monocyclic aryl and heteroaryl group, B is optionally substituted monocyclic nitrogen-containing heterocyclic group, and either a) R1 is hydrogen atom and R2 is group selected out of -NH2 and optionally substituted alkinyl group, or b) R2, R1 and -NH- group with linked R1 form fragment selected out of fragments of formulae , , and , where Ra is selected out of hydrogen atom and group selected out of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, -OR3, where R3 is independently selected out of group including hydrogen atom and lower alkyl or cycloalkyl groups, Rb is selected out of hydrogen atom and group selected out of optionally substituted alkyl or optionally substituted cycloalkyl group; application of claimed compounds in medicine obtainment for treatment of pathological states or diseases, the course of which is alleviated by antagonistic effect on adenosine receptor A2B, and pharmaceutical composition with antagonistic effect on adenosine receptor A2B.

EFFECT: compounds applicable in treatment of such diseases as asthma, bronchostenosis, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal disorders related to cell proliferation, diabetes and/or autoimmune diseases.

26 cl, 49 ex, 2 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,11b-cys-dihydrotetrabenazene of general formula (1) or to its antipode . Invention also relates to composition, to pharmaceutical composition, to application of 3,11b-cys-dihydrotetrabenazene, to method of obtaining 3,11b-cys-dihydrotetrabenazene by i. 1, to compounds of formula (II), (III), as well as to ester of Mosher's acid and 3,11b-cys-dihydrotetrabenazene.

EFFECT: obtaining novel biologically active compounds possessing activity as inhibitor of vesicular carrier of monoamines VMAT2.

23 cl, 12 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of derivatives of 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine of formula [I] as active ingredient for preparation of medication possessing anti-tumor activity, as well as to novel compounds of formula [I'], their pharmaceutically acceptable salts, hydrates and solvates. In formula[I] or [I'] values X1 and X2 are respectively selected from nitrogen atom and carbon atom, group is respectively selected from or . Other radical values are given in invention formula.

EFFECT: compounds can be applied for treatment and prevention of diseases induced by undesirable cell proliferation, such as cancer, rheumatism, etc.

32 cl, 11 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I): , where: R1 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)mOH, group -(CH2)mCN, group -(CH2)mNR9R10; R2 represents hydrogen atom or (C1-C4)-alkyl; R3 represents phenyl, substituted with radicals R6, R7, R8; R4 represents: group ; heterocyclic radical selected from radicals: ; ; ; R5 represents hydrogen atom or (C1-C4)-alkyl; R6, R7 and R8 represent independently on each other hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, cyanogroup, group -(CH2)nNR9R10, group -O-(CH2)mNR9R10; R9 and R10 represent independently on each other hydrogen atom or (C1-C4)-alkyl; or R9 and R10 together with nitrogen atom, to which they are bonded, form heterocyclic radical, selected from pyrrolidin-1-yl, pyperidin-1-yl, morpholin-4-yl or pyperasin-1-yl, substituted or non-substituted in position 4 with (C1-C4)-alkyl; R11 represents hydrogen atom or (C1-C4)-alkyl; R12 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)m-CO-R16; R13 represents hydrogen atom, (C1-C4)-alkyl, phenyl, group NR17R18, group ; R14 represents hydrogen atom, (C1-C4)-alkyl, group -NR17R18; R15 represents hydrogen atom, (C1-C4)-alkyl, group -NR19R20, -COO(C1-C4)-alkyl; R16 represents hydroxyl, (C1-C4)-alkoxy, group -NR9R10; R17 and R18 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R18 can also represent group -COR21, group -SO2R22; R19 and R20 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R20 can also represent (C3-C6)-cycloalkyl, (C3-C6)-cycloalkylmethyl, group -(CH2)mNR9R10; R21 represents (C1-C4)-alkyl, (C3-C6)-Cycloalkyl, group -(CH2)mNR9R10; R22 represents (C1-C4)-alkyl; m equals 1, 2 or 3; n equals 1, 2 or 3. As well as to medication and pharmaceutical composition, to method of obtaining it and its application in therapy.

EFFECT: obtained and described are novel compounds which can be useful in medicine.

14 cl, 67 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) to its salts, in which X is bivalent radical NR2, O; R1 is cyanogroup; n equals 1; R2 is: i) C1-10alkyl, substituted with aryl, where said aryl is substituted with radical -COOR4; or R2 is ii) C1-10alkyl, substituted with radical selected from -O-NR5a-C(=NR5b)-NR5cR5d, -NR7R8, radical

in which each Q1 independently is simple bond, -CH2-; each Q2 independently is O; each R4 independently is hydrogen; each R5a, R5b, R5c, R5d independently is hydrogen; R7 is C1-4alkyl; R8 is arylC1-4alkyl; R11 is aryl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, "Гет"2; each R12 independently is hydroxy, C1-4alkyl; R13a is C1-4alkyl; each R13b is C1-4alkyl; or R2 is iii) radical of formula:

-CpH2p-CH(OR14)-CqH2qR15 (b-3);

CH2-CH2-(O-CH2-CH2)m-OR14 (b-4);

CH2-CH2-(O-CH2-CH2)m-NRI7eR17b (b-5); where in radical (b-3) one of hydrogen atoms in -CpH2p- and one of hydrogen atoms in - CH(OR14)-CqH2q-, which are not part of R14, can be substituted with simple bond or C1-4alkandiyl group; p equals 1, 2 or 3; q equals 0, 1, 2 or 3; each m independently equals 1-10; each R independently is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; R15 is substituent selected from group consisting of NR16aR16, pyrrolidine, pyperidinyl, homopyperidinyl, piperazinyl, , 4-(C1-4alkyl)-piperazinyl, 4-(C1-4alkylcarbonyl)-piperazinyl, 4-(C1-4alkyloxycarbonyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl; R16a and R16b, independently on each other, are hydrogen, C1-6alkyl or C1-6alkyl, substituted with aryl; R17a and R17b, independently on each other, are hydrogen, C1-4alkyl; or R17a and R17b, together with nitrogen atom, to which they are bonded, form pyrrolidine, morpholinyl; each R18 independently is arylC1-4alkyl; R19 is hydrogen; R3 is nitrogroup; aryl is phenyl; "Гет"2 is piridyl. Invention also relates to pharmaceutical composition, to method of obtaining compound on any of ii 1-4, as well as to compounds of formula (IV-a), (IV-b),(V).

EFFECT: obtaining novel biologically active compounds possessing ability to inhibit HIV.

11 cl, 18 ex, 3 tbl

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology and design of agents with immunomodulating properties. A new fungal strain Penicillium verrucosum VKPM F-984 and a new immunomodulating agent based on the strain are proposed. The strain is extracted from microflora of ginseng roots and is kept in a medium which contains mineral salts, glucose and asparagine. Fungus mycelium is extracted with a water-alcohol solution (70% ethanol solution). The advantage of this agent is its natural occurrence and effecient stimulation of adaptive capabilities of the body.

EFFECT: obtaining an extract which has stimulating action on cell and humoral immunity, improves immune status of the body.

3 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: in formulas (I) and (Ia) . A is 1-cyclopentene-1,2-diyl; Z1 and Z2 are O; E is phenyl substituted with 1-4 substituting groups selected from halogen, Y is phenyl substituted with 1-2 substituting groups selected from halogen, C1-C6alcoxy, halogen C1-C6alcoxy; the meaning of other radicals are indicated in the formula of the invention. The invention refers also to the pharmaceutical composition including the compound of the invention, to the application of the said compound at preparation of the medicinal agent and to the application for DHODH inhibition.

EFFECT: compound of the present invention can find application as medicinal agent inhibiting dehydroorotate dehydrogenase.

9 cl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to occupational diseases, and can be used for correction of immune alterations in persons being in contact with toxic substances. The method is carried out as follows. Introduction of immunostimulant Cyclopheron is preceded with individual adverse effect test by incubation in vitro of Cyclopheron and mononuclear cells separated from peripheral blood. Cyclopheron is introduced provided CD19+ B-lymphocyte count is exceeded by 20% and more, and activated HLA-DR+ lymphocyte count by 15% and more.

EFFECT: method allows improving effectiveness of correction of immune alterations owing to prediction of body's immune response to Cyclopheron therapy.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.

EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.

19 cl, 50 dwg, 4 tbl, 43 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely, to surgical stomatology and can be used at treatment of septic wounds of maxillofacial area. For this purpose the 4.16% cycloferon immunomodulator solution, prepared by its dilution with the 0.9% sodium chloride solution is injected into an exudative phase of a septic wound process against complex medicamental treatment in a wound on turundas. In case of the expressed exudation, the cycloferon solution is diluted with the 10% sodium chloride hypertonic solution. Dressings are performed daily. In a proliferative phase of a wound process cycloferon is injected into a wound a kind of 5% liniment, thus dressings are performed in a day. The way allows raising efficiency of complex treatment of patients with the given pathology without system influence on immune system at the expense of local cycloferon immunocorrection taking into account wound process phases.

EFFECT: increase of efficiency of complex treatment of patients with the given pathology without system influence on immune system at the expense of local cycloferon immunocorrection taking into account wound process phases.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely odontology and can be used for treatment of pyoinflammatory diseases of soft tissues of maxillofacial area. The way is carried out as follows. Roncoleukin is administered in the exudative-inflammatory phase of a purulent wound process in the form of a solution with 500000 ME dose of active substance, into a wound preliminary irrigated by means of 10.0 ml of sterile 0.9% sodium chloride, on the turundas, dilluted either with 0.9%, or 10% sodium chloride solution. Thus a bandage from 20% dimexid solution is imposed on periphery of a purulent wound, spending daily dressings. In a proliferative phase - an irrigation of a wound using the Roncoleukin solution is combined with 500000 ME dose of active substance, diluted with 0.9% solution of sodium chloride and salve dressings with preparations on a water-soluble basis; dressings are spent in a day. The way allows normalising indicators of local immunity of a purulent wound and an oral cavity, to strengthen functional activity of phagocytes of a wound, to accelerate purification of wounds from necrotic masses, to optimise terms of occurrence of granulations.

EFFECT: possibility to normalise indicators of local immunity of a purulent wound and an oral cavity, to strengthen functional activity of phagocytes of a wound, to accelerate purification of wounds from necrotic masses, to optimise terms of occurrence of granulations.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, and can be used for treatment of calicivirus intestinal infection at children. For this purpose simultaneously with symptomatic therapy children's anaferon is prescribed perorally. In the first days of disease anaferon is prescribed in a dose of 0.3 g each 30 minutes within 2 hours. Then 3 more tablets of 0.3 g at regular intervals. The next 4 days it is prescribed in a dose of 0.3 g 3 times a day.

EFFECT: reduction of terms of treatment at the expense of stimulation of development of endogenous interferons and activation of process of development of specific antibodies, restoration in short terms of a gastroenteric tract microbiocenosis.

2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new pyrrolopyrimidinone derivatives with formula (I) and their pharmaceutically used salts, with inhibition properties towards GSK-3, as well as to intermediate compounds with formula (Ic). In compounds with formula (I) and formula (Ic)

A1 is -(CH2)2- or -(CH2)3-; A is a single bond or a group, which links A1 and G1 in form of A1 -C(=O)-G1, A1- (C=O)-O-G1, A1 -(C=O)-NR101-G1, A1-O-(C=O)-G1, A1 -NR104-G1, A1-NR105-(C=O)-G1, A1-NR106-S(=O)2-G1, A1-NR107-(C=O)-O-G1 or A1-NR108-(C=O)-NR109-G1; G1 is a single bond or a bivalent group, which can be obtained through removal of two hydrogen atoms from any alicyclic hydrocarbon with 3-6 carbon atoms, phenylene, monocyclic or cyclic aromatic heterocyclic compound with 2-9 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N, or monocyclic heterocyclic compound 2-6 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N; A3 is a single bond or bivalent acyclic aliphatic hydrocarbon group with 1-3 carbon atoms, which links G1 with A4 of the same or different carbon atom; A4 is a single bond or a group, which links A3 with G2 in form of A3-C(=0)-G2, A3-C(=0)-0-G2, A3-C(=0)-NR121-G2, A3-O-G2, A3-NR124-G2, A3-NR125-C(=0)G2 or A3-S-G2. Description of other radical is given in the formula of invention.

EFFECT: compounds can be used in treating such diseases as diabetes, neurodegenerative diseases and others.

43 cl, 3 tbl, 513 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, particularly to immunology, and concerns treatment of rheumatoid arthritis associated with inadequate response to TNF-alpha inhibitor. The treatment is ensured by intravenous introduction of antibodies bound with CD20, particularly humanised 2H7v16, containing variable domains presented with SEQ ID Nos. 1 and 2. Antibodies are injected intravenously in dosage 1000 mg twice.

EFFECT: effective treatment of arthritis associated with inadequate response to TNF-alpha inhibitor due to introduction regimen developed by the applicant, extension of range of medical products for treatment of said pathology.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new biologically active high-immunotropic compound -N,N'-(sulphonyldi-1,4-phenylene)bis[(N",N'"-dimethyl)methyliminomethane]1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-5-pyrimidinesulphonate of formula stated below to be used in treatment of, e.g., patients suffering from leprosy, allergic dermatosis, dermatitis herpetiformis. .

EFFECT: new compound is characterised with useful biological activity.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

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