Imidazoquinolines, pharmaceutical preparation and method for induction of cytokine biosynthesis based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

 

The present invention relates to imidazolinones connections with sulfonamidnuyu or sulfa substitution in position 1, and to pharmaceutical preparations containing these compounds. In addition, the present invention relates to the use of these compounds as immunomodulators, inducing the biosynthesis of cytokines in animals and in the treatment of various pathologies, including viral and neoplasticeskih diseases.

In the first deserving trust the message cyclical 1H-imidazo[4,5-C]quinoline, Bachman and others (Backman et al., J.Org.Chem. 15, 1278-1284 (1950)) describe the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline for possible use as antimalarials. Subsequently, described the synthesis of various substituted 1H-imidazo[4,5-C]quinoline. For example, Jane and others (Jain et al., J.Med.Chem. 11, pp.87-92 (1968)) was synthesized compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline for use as an anticonvulsant and cardiovascular drugs. Baranov and others (Baranov et al., Chem.Abs. 85, 94362 (1976)also reported several 2-accomidate[4,5-C]quinoline, and Bereni and others (Berenyi et al., J. Heterocyclic Chem., 18, 1537-1540 (1981)has described some 2-accomidate[4,5-C]quinoline.

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

As can be seen, for example, from WO 98/30562, EP 894797 and WO 00/09506, interest cyclic imidazoquinolines systems is maintained. EP 894797 describes amidoamine imidazopyridine compounds that can be used as immunomodulators, while WO 00/09506 describes imidazoquinolines compounds containing sulfonamidnuyu Deputy, in which sulfonamidnuyu nitrogen is part of a saturated heterocyclic ring. However, still a need for compounds capable of modulating the immune response, inducing the biosynthesis of cytokines or activates other mechanisms.

We have discovered a new class of compounds that can be used for induction in animals biosynthesis of cytokines. Accordingly, the present invention is represented by compounds of the Formula I:

where R, R1and R2defined below.

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

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

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

As mentioned above, in the present invention is represented by compounds of the Formula I:

where

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

R1is-alkyl-NR3-SO2-X-R4;

X is a bond or-NR5-;

R4is phenyl, naphthyl, thienyl, chinoline, ethenolysis; tetrahydroquinolines, thiazolyl, oxazolyl, pyrazolyl, piperazinil, piperidinyl, thiomorpholine, pyrrolidine, alkyl or alkenyl each of which may be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

is phenyl, substituted NO2;

- O-alkyl;

- COOH;

- CO-O-alkyl;

- (O) 0-2-alkyl;

- (alkyl)0-1-NR3R3;

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

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

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

- halogen;

- halogenated;

- halogenoalkanes;

- CO-halogenoalkanes;

- NO2;

- CN; and in the case of alkyl, oxoprop;

R2is selected from the group which consists of:

is hydrogen;

- alkyl;

is phenyl;

- alkyl-O-alkyl; and

- alkyl, substituted by one or more substituents chosen from:

is phenyl, substituted by alkoxyl;

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

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

n is a number 0

or its pharmaceutically acceptable salt.

Getting connections

Aminoisoquinoline of the present invention can be obtained according to reaction Scheme I where R, R1, R2and n are defined above.

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

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

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

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

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

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

A reaction scheme I

Connection of infusion is his invention, in which R1is a sulfonamide, can also be obtained in accordance with reaction Scheme II, where R1, R2, R4and n are defined above, and m is a number from 1 to 20.

According to reaction Scheme II aminoalkylsilanes 1 N-imidazo[4,5-C]quinoline-4-amine of Formula VII interacts with sulphonylchloride Formula IX with the formation of the compounds of Formula X, which is a variant of Formula I. the Reaction can be conducted at room temperature in such an inert solvent as dichloromethane, in the presence of such bases as pyridine or N,N-diisopropylethylamine. Many 1H-imidazo[4,5-C]quinoline-4-amines is known compounds, see, for example, U.S. patent No. 6069149 (Namba (Namba)); other easily obtained well-known synthetic methods. Many sulphonylchloride Formula IX are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

A reaction scheme II

Compounds of the present invention, in which R1is a sulfonamide, can also be obtained in accordance with reaction Scheme III, where R1, R2, R4and n are defined above, a m is a number from 1 to 20.

According to reaction Scheme III aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VII interacts with a sulfonic anhydride of the acid of Formula XI with the formation of the compounds of Formula X, which is one of the variants of the Formula I. the Reaction can be conducted at room temperature in such an inert solvent as dichloromethane, in the presence of such bases as pyridine or N,N-diisopropylethylamine. The reaction can also be performed at room temperature in acetonitrile. Many anhydrides, sulfonic acids of the Formula XI are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

A reaction scheme III

Tertiary sulfonamides of the present invention can also be obtained according to reaction Scheme IV, where R1, R2, R3, R4and n are defined above, a m is a number from 1 to 20.

According to reaction Scheme IV aminoalkylsilanes 1 N-imidazo[4,5-C]hyalinization Formula X interacts with the halide of Formula XII with the formation of compounds of Formula XIII, which is a variant of Formula I. the Reaction can be conducted at room temperature by adding to a solution of the compounds of Formula X in N,N-dimethylformamide first, sodium hydride, and then the halide in such an inert solvent as dichloromethane, in the presence of such bases as pyridine or N,N-diisopropylethylamine. Many halides of the Formula XII I have are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

A reaction scheme IV

Compounds of the present invention, in which R1contains sulfa group, can be obtained according to reaction Scheme V, where R1, R2, R4, R5and n are defined above, a m is a number from 1 to 20.

At the stage (1) of reaction Scheme V aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with sulfurylchloride in the place of sulfhemoglobin Formula XIV. The reaction can be conducted by adding a solution of sulfurylchloride in dichloromethane to a solution of the compounds of Formula VIII dichloromethane in the presence of one equivalent of 4-(dimethylamino)pyridine. The reaction is preferably carried out at low temperature (-78°). Upon completion of addition, the reaction mixture can be heated to room temperature.

At stage (2) of reaction Scheme V amine of Formula R5R4NH interacts with sulfhemoglobin Formula XIV with the formation of 1H-imidazo[4,5-C]hyalinella Formula XV, which is a variant 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 react the availability of the mixture from stage (1). Add the solution is preferably at ponizhennoi temperature (-78°). Upon completion of addition, the reaction mixture can be heated to room temperature. The product or its pharmaceutically acceptable salt produce using conventional methods.

The reaction scheme V

Tetrahydroisoquinoline of the present invention can be synthesized according to reaction Scheme VI, where R2, R3, R4and R5defined above, a m is a number from 1 to 20.

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

On stage (2A) of reaction Scheme VI aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of Formula XVII interacts with the formation of compounds of Formula XVIII, which is one of the variants of the Formula I. If R3is hydrogen, the reaction can be carried out the ü in one stage using methods described in the above Schemes reactions II and III, using tetrahydroisoquinoline Formula XVII instead of imidazoquinolines Formula VIII. If R3is not hydrogen, the reaction can be performed in two stages, the first stage is carried out using the methods described in the above Schemes reactions II and III, and the second stage is conducted by the method in accordance with reaction Scheme IV, using tetrahydroisoquinoline analog imidazoquinolines. The product or its pharmaceutically acceptable salt produce using conventional methods.

On stage (2b) of reaction Scheme VI aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of Formula XVII interacts with the formation of compounds of Formula XIX, which is one of the variants of the Formula I. the Reaction can be carried out by the method described in reaction Scheme V, using tetrahydroisoquinoline Formula XVII instead of imidazoquinolines Formula VIII. The product or its pharmaceutically acceptable salt produce using conventional methods.

The reaction scheme VI

Tetrahydroisoquinoline of the present invention can also be synthesized according to reaction Scheme VII, where R, R2, R3, R4, R5and n are defined above, a m is a number from 1 to 20.

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

Stage (2A) and (2b) can be a method similar to those shown in reaction Scheme VI.

The reaction scheme VII

Some compounds of Formula 1 can be easily obtained from other compounds of Formula I. for Example, compounds in which the substituent R4contains choralcelo group can interact with the amine with the formation of the substituent R4substituted secondary or tertiary amino group; compounds in which the substituent R4contains a nitro-group can be restored to compounds in which the substituent R4contains a primary amine.

In the framework of the present invention, terminii “alkyl”, “alkenyl”, “quinil” and the prefix “-Ala” refers to both linear and branched, and cyclic groups, i.e. cycloalkyl and cycloalkenyl group. Unless Ino is, these groups contain from 1 to 20 carbon atoms, whereas alkeneamine and alkyline groups contain from 2 to 20 carbon atoms.

Preferred groups containing up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably contain from 3 to 10 carbon atoms included in the cycles. Examples of cyclic groups can be cyclopropyl, cyclohexyl and substituted.

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

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

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

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

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

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

Pharmaceutical preparations and biological activity

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

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

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

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

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

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

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

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

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

Example 1

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate

5-Dimethylamino-1-naphthalenesulfonate (1,82 g, 6,74 mmol) was added to a mixture of N,N-diisopropylethylamine (1.23 ml, 7,06 mmol), dichloromethane (15 ml) and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (2.0 g, 6.42 per mmol). The reaction mixture is left overnight to mix at room temperature. To the mixture was added methanol to obtain a clear Rast is ora. To the reaction mixture was added silica gel, and then removing the solvent. The silica gel was placed in a column, and then elute with chloroform step-by-step gradient to the ratio of chloroform / methanol 9:1. The resulting product is recrystallized from N,N-dimethylformamide and deionized water, highlighting 2.5 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate in the form of a yellow crystalline substance with a melting point p.223-224°C. Elemental analysis: calculated for C30H36N6About2S: %66,15; %N 6,66; %N 15,43; Experimentally found: %Collected 66.36; %N 6,34; %N 15,23.

Example 2

N1-[4-(4-Amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate

A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (0.5 g, 2.0 mmol) in pyridine (250 ml) is heated to 60°to dissolve the amine.

The solution is allowed to cool to about 30°S, and then slowly added 5-dimethylamino-1-naphthalenesulfonate (0.5 g, 1.8 mmol). After 1 hour, add another 0.3 g of 5-dimethylamino-1-naphthalenesulfonate. The reaction mixture is heated to 60°and at this temperature, leave overnight. The reaction mixture is concentrated under vacuum. The residue is recrystallized from propyl. Output: solid N1-[4-(4-am is but-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate with a melting point 200-201° C.

Example 3

N2-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-2-thiophenesulfonyl

2-Thiophenesulfonyl (0.3 g in 10 ml of dichloromethane, 1.6 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (0.5 g, 1.6 mmol) in dichloromethane (40 ml) and pyridine (0.8 ml). Within a few hours the reaction mixture was kept at room temperature, and then add an additional portion of 2-thiophenesulfonyl (0.1 g, 0.6 mmol). The reaction mixture was left overnight, and then concentrated under vacuum. The resulting residue is purified column chromatography under pressure (silica gel, 9/1 dichloromethane / methanol), and the fractions containing the product is washed with saturated aqueous sodium bicarbonate. The organic layer is dried (gSO4), filtered, and after concentration obtained 0.2 g of N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-2-thiophenesulfonyl in the form of a white powder with a melting point 137,5-141,5°C. NMR1H (300 MHz, DMSO-D6) δ 8,00 (doublet, J=8.0 Hz, 1H), 7,89 (double doublet, J=5.0 and 1.3 Hz, 1H), 7,83 (Shir. S., 1H), to 7.61 (double doublet, J=8,3, 1.1 Hz, 1H), 7,54 (double doublet, J=3,7, 1.3 Hz, 1H), 7,42 (triplet, J=7,2 Hz, 1H), 7,25 (cf., 1H), 7,15 (cf., 1H), 6,44 (Shir. S., 2H), 4,47 (triplet, J=7,4 Hz, 2H), 2,87 (cf., 4H), 1,80 (cf., 4H), 1,58-1,38 (cf., 4H), 0,96 (triplet, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 317, 3091, 2957, 2933, 2870, 1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761, 733 cm-1; Mass spectrometry (electron impact) m/e 457,1606 (457,1606 calculated for C22H27N5O2S2); Elemental analysis: theory. for C22H27N5O2S2With 57,74; N - 5,95; N - 15,30; exp.: WITH - 57,50; N IS 5.98; N - BR15.15.

Example 4

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

2-Toluensulfonate (0.5 g in 10 ml of dichloromethane, 2.7 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (0.75 g, 2.4 mmol) in dichloromethane (115 ml) and pyridine (1 ml). Within 4 hours the reaction mixture was kept at room temperature, and then concentrated under vacuum. The resulting residue is purified column chromatography under pressure (silica gel, 9/1 dichloromethane / methanol, Rf0,16). The fractions containing the product are combined and washed with saturated aqueous sodium bicarbonate. The organic layer is dried (gSO4), filtered and concentrated. After the final recrystallization from a mixture of dichloromethane with diethyl ether to obtain 0.65 g of N-[4-(4-amino-2-butyl-1 H-imidazo[4,5-C]quinoline-1-yl)butyl]-phenylmethanesulfonyl in the form of a white powder with a melting point 197,0-199,5°C. NMR1H (300 MHz, DMSO-D6) δ 8,02 (doublet, J=7,6 Hz, 1H), 7.62mm (on oinoi doublet, J=8,3, 1.1 Hz, 1H), 7,42 (double triplet, J=7,5, 1.1 Hz, 1H), 7,35-7.23 percent (cf., 1H), 7,12 (triplet, J=5.4 Hz, 1H), 6,46 (Shir. S., 2H), 4,49 (triplet, J=7.5 Hz, 2H), 4,29 (S., 2H), 2.91 in (cf., 4H), 1,83-1,42 (cf., 8H), 0,96 (triplet, J=7.4 Hz, 3H); IR (KBr) 3460, 3293, 3226, 3158, 2955, 2931, 2867, 1632, 1586, 1534, 1482, 1437, 1389, 1331, 1152, 1094, 752, 700 cm-1; Mass spectrometry (electron impact) m/e 465, 2204 (465, 2198 calculated for C26H31N5O2S); Elemental analysis: theory. for C25H31N5O2S: 64,49; N - Of 6.71; N - 15,04; exp.: WITH - 64,15; N - OF 6.71; N - 15,00.

Example 5

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-benzosulfimide

2-Benzosulphochloride (0.45 ml in 10 ml of dichloromethane, 3.5 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (1.0 g, 3.2 mmol) in dichloromethane (140 ml) and pyridine (0.8 ml). Within 4 hours the reaction mixture was kept at room temperature, and then concentrated under vacuum. The resulting residue is purified column chromatography under pressure (silica gel, 9/1 dichloromethane / methanol, Rf0,28) followed by recrystallization from a mixture of dichloromethane with diethyl ether. Output: 1,14 g N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-1-benzosulfimide in the form of a white powder with a melting point of 75.5-79,0°C. NMR1H (300 MHz, DMSO-D6) δ 7,99 (doublet, J=7.7 Hz, 1 is), 7,76 (doublet, J=7,2 Hz, 1H), 7,63-7,53 (cf., 5H), 7,42 (cf., 5H), 7,25 (cf., 1H), gold 6.43 (Shir. S., 2H), 4,45 (triplet, J=7,6 Hz, 2H), 2,87 (triplet, J=7.7 Hz, 2H), 2,78 (cf., 2H), 1,79 (cf., 4H), 1,55-1,40 (cf., 4H), 0.95 (triplet, J=7.4 Hz, 3H); Mass spectrometry (electron impact) m/e 451,2036 (451,2042 calculated for C24H29N5O2S); Elemental analysis: theory. for C24H29N5O2S: 63,83; N - 6,47; N - 15,51; exp.: WITH - 63,89; N - 6.42 PER; N - 15,30.

Example 6

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

Methanesulfonyl anhydride (0.6 g, 3.4 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (1.0 g, 3.2 mmol) in acetonitrile (200 ml). After a few minutes a precipitate. The solvent is removed under vacuum and the residue separated between dichloromethane and saturated aqueous sodium bicarbonate. Fraction is separated, and the organic fraction dried (MgSO4), filtered and concentrated. Obtained crude solid product is white. After recrystallization from methyl acetate get a white crystalline N-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]methanesulfonamide with a melting point 195,1-196,0°C. NMR1H (300 MHz, DMSO-D6) δ 8,04 (doublet, J=7,4 Hz, 1H), to 7.61 (double doublet, J=8,3, 1.2 Hz, 1H), 7,50 (double triplet, J=7,5, 1.1 Hz, 1H), 7,26 (double triplet, J=7,5, 1.2 Hz, 1H, 6,99 (triplet, J=5.7 Hz, 1H), 6,44 (Shir. C., 2N), to 4.52 (triplet, J=7.5 Hz, 2H), 3.02-2,86 (cf., 7H), 1,82 (cf., 4H), 1,62 (cf., 2H), 1,46 (quadruplet, J=7,4 Hz, 2H), 0,96 (triplet, J=7.4 Hz, 3H); IR (KBr) 3348, 3299, 3152, 2952, 2931, 2869, 1642, 1584, 1530, 1480, 1323, 1155, 1142, 1094, 982, 765 cm-1; Mass spectrometry (electron impact) m/e 389, 1889 (389, 1885 calculated for C19H27N5O2S);

Elemental analysis: theoretical. for C19H27N5O2S: 58,59; N - 6,99; N - 17,98; exp. WITH - 58,26; N-6,64; N-17,69.

Example 7

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-3-nitro-1-benzosulfimide hydrochloride

In accordance with the General procedure described in Example 5, 3-nitrobenzenesulfonamide connect with 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-nitro-1-benzosulfimide isolated in the form of chlorhydrate salt (white solid) with a melting point 176,0-178,2°C. NMR1H (300 MHz, DMSO-D6) δ 8.70 (PTS. Shir., S., 2H), 8,49-8,42 (cf., 2H), 8,21-8,17 (cf., 2H), 8,06 (triplet, J=5.7 Hz, 1H), 7,88-7,81 (cf., 2H), 7,71 (triplet, J=7.7 Hz, 1H), EUR 7.57 (triplet, J=7.7 Hz, 1H), 4,56 (triplet, J=7,3 Hz, 2H), 2,94 (triplet, J=7.7 Hz, 2H), 2,86 (cf., 2H), 1,81 (cf., 4H), 1.60-to 1,42 (cf., 4H), 0,96 (triplet, J=7,3 Hz, 3H); IR (KBr) 3096, 2954, 2771, 1671, 1607, 1528, 1351, 1335, 1163, 1128, 1083, 879, 758, 735, 672, 661 cm-1; Mass spectrometry (electron impact) m/e 496,1897 (496,1893 calculated for C24H 28N6O4S); Elemental analysis: theory. for C24H28N6O4S·HCl·H2O: - at 52.31; H 5.67; N - 15,25; exp.: With - 52.26; H 5.46; N - 15,09.

Example 8

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-amino-1-benzosulfimide hydrochloride

To a solution of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-nitro-1-benzosulfimide hydrochloride (0.4 g) in methanol (250 ml) upload a catalytic amount of 10% palladium on coal (of 0.085 g). The reaction mixture is placed in an atmosphere of hydrogen (50 psi; 3,44·105PA) and shaken for 2 hours in a Parr apparatus. Then the reaction mixture is filtered and the solvent is removed under vacuum. After recrystallization of the solid product from propanol-2 obtain 0.18 g of a yellowish-white crystalline N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-amino-1-benzosulfimide hydrochloride with a melting point 110,2°C (decomp.). NMR1H (300 MHz, DMSO-D6) δ 8,70 (PTS. Shir., S., 2H), by 8.22 (doublet, J=8,2 Hz, 1H), 7,83 (doublet, J=7.8 Hz, 1H), 7,72 (triplet, J=7,6 Hz, 1H), to 7.59 (triplet, J=7.7 Hz, 1H), 7,43 (triplet, J=5,9 Hz, 1H), 7,15 (triplet, J=7.9 Hz, 1H), 6,95 (triplet, J=1.9 Hz, 1H),6,84 (doublet, J=7.7 Hz, 1H)that was 6.73 (double doublet, J=8,0, 1.5 Hz, 1H), 5,63 (width, S., 2H), 4,56 (triplet, J=7.5 Hz, 2H), 2,77 (quadruplet, J=6.3 Hz, 2H), 1,83 (cf., 4H), 1.60-to 1,40 (cf., 4H), 0,97 (triplet, =7,3 Hz, 3H); IR (KBr) 3313, 3135, 2957, 2870, 2782, 1671, 1599, 1485, 1454, 1313, 1155, 1084, 754, 735, 686 cm-1;

Mass spectrometry (electron impact) m/e 466,2150 (466, 2151 calculated for C24H30N6O2S); Elemental analysis: theory. for C24H30N6O2S·HCl·0,25H2O: 56,79; N - 6,26; N - 16,56, Cl - 6,98; exp.: With - 56,87; N - 6,22; N - 16,19, Cl - 7,22.

Example 9

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-nitro-1-benzosulfimide hydrochloride

In accordance with the General procedure described in Example 5, 4-nitrobenzenesulfonate connect with 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-nitro-1-benzosulfimide isolated in the form of chlorhydrate salt (white solid) with a melting point 96,0°C (decomp.). NMR1H (300 MHz, DMSO-D6) δ 8,70 (PTS. Shir., S., 2H), scored 8.38-8.34 per (cf., 2H), 8,19 (doublet, J=8,2 Hz, 1H), 8,09 (triplet, J=5.6 Hz, 1H), 8,03-7,99 (cf., 2H), 7,80 (doublet, J=7,4 Hz, 1H), 7,68 (triplet, J=7,4 Hz, 1H), 7,54 (triplet, J=7,2 Hz, 1H), 4,55 (triplet, J=7,4 Hz, 2H), 2,94 (triplet, J=7.7 Hz, 2H), 2,86 (quadruplet, J=6.2 Hz, 2H), 1,80 (cf., 4H), 1,58 (cf., 4H), 1,45 (quadruplet, J=7.5 Hz, 2H), 0,96 (triplet, J=7,3 Hz, 3H); IR (KBr) 3283, 3100, 2957, 2870, 2782, 1670, 1606, 1528, 1347, 1311, 1162, 1092, 854, 746, 737, 686 cm-1; Mass spectrometry (electron impact) m/e 496, 1902 (496, 1893 calculated for C24H28N6O4S); Elements of the economic analysis: theory. for C24H28N6O4S·Hcl·0,N2O: 52.57; H 5.64; N - 15,33; exp.: With - 52.57; H 5.46; N - 15,33.

Example 10

N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-4-amino-1-benzosulfimide hydrochloride

To a solution of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-nitro-1-benzosulfimide hydrochloride (0,38 g) in methanol (250 ml) upload a catalytic amount of 10% palladium on coal (of 0.085 g). The reaction mixture is placed in an atmosphere of hydrogen (50 psi; 3,44·105PA) and shaken for 2 hours in a Parr apparatus. The reaction mixture is filtered and the solvent is removed under vacuum. After recrystallization of the solid product from propanol-2 obtain 0.34 g yellowish-white powder N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-amino-1-benzosulfimide hydrochloride with a melting point 203,1-205,0°C. NMR1H (300 MHz, DMSO-D6) δ 8,65 (PTS. Shir, C., 2H), 8,21 (doublet, J=8.0 Hz, 1H), 7,82 (cf., 1H), 7,71 (triplet, J=7.7 Hz, 1H), 7,58 (triplet, J=7.7 Hz, 1H), 7,38 (doublet, J=8.7 Hz, 1H), 7,13 (triplet, J=5,9 Hz, 1H), 6,60 (doublet, J=8.7 Hz, 1H), of 5.92 (width, S., 2H), 4,55 (triplet, J=7,6 Hz, 2H), 2,96 (triplet, J=7,6 Hz, 2H), 2,70 (quadruplet, J=6,4 Hz, 2H), 1,81 (cf., 4H), 1,58 was 1.43 (cf., 4H), 0,96 (triplet, J=7.4 Hz, 3H); IR (KBr) 3430, 3316, 3215, 3046, 2955, 2868, 2679, 1671, 1594, 1334, 1157, 1091, 851, 776, 759 cm-1; Mass spectrometry (UD e is p) m/e 466,2145 (466,2151 calculated for C 24H30N6O2S); Elemental analysis: theory. for C24H30N6O2S·HCl: 57,30; N - 6,21; N - 16,71; exp.: WITH - 57,36; N. OF 6.31;N - 16,21.

Example 11

N5-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-5-ethynodiolthinyl

Suspension isoquinoline-5-sulphonylchloride hydrochloride (0,83 g in 50 ml of pyridine, 3.1 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (1.0 g, 3.2 mmol) in dichloromethane (175 ml). The solution becomes bright yellow color, and within 4 hours it stand at room temperature. Add another 0.18 g isoquinoline-5-sulphonylchloride hydrochloride and support reaction for a further 60 hours. The yellow solution is concentrated under vacuum, dissolved in dichloromethane and successively washed with saturated aqueous sodium bicarbonate and water. The organic fraction is dried (gSO4), filtered and concentrated under vacuum. The resulting residue is purified column chromatography under pressure (silica gel, 9/1 dichloromethane / methanol). Yield: 0.7 g of N5-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-ethynodiolthinyl in the form of a white powder with a melting point 96,0°C (decomp.). NMR1H (300 MHz, DMSO-D6) δ 9,44 (doublet, J=0.7 Hz, 1H), 8,64 (doublet, J 6,1 Hz, 1H), to 8.41-8,35 (cf., 2H), 8,30 (double Doo the years, J=7,4, 1.2 Hz, 1H), 8,11 (triplet, J=5.6 Hz, 1H) 7,92 (doublet, J=7,6 Hz, 1H), 7,75 (doublet, J=7.7 Hz, 1H), to 7.61 (double doublet, J=8,3, 1.2 Hz, 1H), 7,41 (double triplet, J=7,7, 1.2 Hz, 1H), 7,22 (double triplet, J=7,6, 1.2 Hz, 1H), 6,47 (Shir. C., 2N), to 4.38 (triplet, J=7.5 Hz, 2H), 2,86-2,74 (cf., 4H), 1,78-1,63 (cf., 4H), 1,50-1,34 (cf., 4H), 0,94 (triplet, J=7.4 Hz, 3H); Mass spectrometry (electron impact) m/e 502,2151 (502,2151 calculated for C27H30N6O2S); Elemental analysis: theory. for C27H30N6O2S: 64,52; N - Of 6.02; N - 16,72; exp.: WITH - 64,03; N - 6,03; N - 16,55.

Example 12

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

Methanesulfonyl anhydride (0,19 g, 1.1 mmol) was added dropwise with stirring to a solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-4-amine (1.0 g, 3.2 mmol) in dichloromethane (75 ml) and acetonitrile (100 ml). The reaction is maintained for 60 hours at room temperature. The solvent is removed under vacuum and the residue is purified column chromatography under pressure (silica gel, 9/1 dichloromethane / methanol). The fractions containing the product are combined and washed with saturated aqueous sodium bicarbonate, dried (gSO4), filtered and concentrated. Output: N-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl)butyl]methanesulfonamide in the form of a white solid with a melting point 78,1-9,5° C. NMR1H (300 MHz, DMSO-D6) δ 7,99 (doublet, J=7,6 Hz, 1H), 7.62mm (double doublet, J=8,3, 1.2 Hz, 1H), 7,42 (cf., 1H), 7,27-7,21 (cf., 3H), 6,98 (triplet, J=5.7 Hz, 1H), 6.89 in (doublet, J=8.7 Hz, 1H), 6,58 (Shir. s, 2H), 4,45 (Shir. S., 2H), 4,33 (S., 2H), 3.72 points C., 3H), 2,87 (cf., 5H), 1.55V (Shir. C., 2N; Mass spectrometry (chemical ionization (HEE)) m/e 454 (M+H).

Example 13

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

A solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-4-amine (9,3, 36 mmol) in 10 ml dichloromethane in a test tube with screw cap cooled to -5°C. Add butanesulfonate (45 µmol) in the form of a 0.3 M solution in dichloromethane; during the addition and for 15 seconds after it passed through the mixture argon. The mixture is left overnight at -5°C. Add aminomethane polystyrene resin (approximately 90 mg of 0.62 mEq/g, 100-200 mesh, F. “Bachem” (Bachem)and the mixture is heated to boiling and shaken at 600 rpm for 3 hours. In order to remove the resin, the mixture is filtered through a column of Poly-Prep (Bio-Rad No. 731-1550). The solvent is removed under vacuum and the residue purified by the method prepreparation liquid chromatography system of Gilson (Gilson) (column Rainin Microsorb C18, 21,4×250 mm, particle size 8 μm, the pores 6010 ml/min, gradient elution from 2 to 95% B over 25 min is t, 5 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. The solid is dissolved in approximately 3 ml of a mixture of dichloromethane / methanol 2/1 and to isolate the free amine, within 2 hours shaken with 80 mg (300 μmol) diisopropylaminomethyl-polystyrene resin (Argonaut PS-DIEA, 3,86 mmol/g)and then filtered, and the solid product dried under vacuum. Mass spectrometry (chemical ionization at atmospheric pressure (head)) m/e 376,16 (M+H).

Example 14

N1-{4-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetranitro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-fluoro-1-benzosulfimide

In accordance with the General procedure described in Example 5, 1-(4-aminobutyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine connect with forbindelsesfanebladet. After recrystallization from a mixture of n-propyl / methanol 4/1 get a white crystalline N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-fluoro-1-benzosulfimide with a melting point 191,0-193,0°C. NMR1 H (300 MHz, DMSO-D6) δ 7,86-7,81 (cf., 2H), 7,45-7,39 (cf., 2H), 5,65 (Shir. S., 2H), 4,15 (cf., 2H), 3,76 (triplet, J=6,7 Hz, 2H), 3.27 to (cf., 3H), 3.00 and (triplet, J=6,7 Hz, 2H), 2,90 (Shir. S., 2H), 2,78 (cf., 2H), 2,65 (Shir. S., 2H), 1,75 (Shir. C., 4H), 1,61 (cf., 2H), 1,43 (cf., 2H); Mass spectrometry (HEE) m/e 476 (M+H); Elemental analysis: theory. for C23H30FN5O3S: %58,09; %N 6,36; %N 14,73; exp.: %58,37; %N 6.35MM; %N 14,60.

Example 15

N1-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-fluoro-1-benzosulfimide

Part a

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

Part B

The triethylamine (7,26 g of 71.7 mmol) was added to a solution of the material obtained in part a, in ethanol and in 2 days refluxed. The reaction mixture was concentrated and get syrupy liquid orange. Chromato-mass-spectrometric analysis of this liquid showed in the content as the target product, and the source material is. The liquid was dissolved in dichloromethane (100 ml) and cooled in an ice bath. Add trimethylamine (5 ml) and benzoyl chloride (1.9 ml). The reaction mixture was kept at room temperature for 2 days, and the analysis performed at this point using high-performance liquid chromatography (HPLC) showed that the reaction was not completed. The reaction mixture is concentrated under vacuum. The residue is dissolved in isopropyl alcohol (150 ml). Add trimethylamine (5 ml), and leave the reaction for the night to boil under reflux. The reaction mixture is concentrated under vacuum. The residue is purified column chromatography under pressure (silica gel; elution with 10% methanol in dichloromethane). Containing the product fractions are combined and concentrated under vacuum. After recrystallization of the residue from acetonitrile obtain 6.7 g of a solid of tert-butyl N-[4-(2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 158-159°C.

Part b

Chloroperoxybenzoic acid (1.05 equivalents 65%) is slowly added in small portions to a solution of tert-butyl N-[4-(2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate (6,56 g of 15.75 mmol) in dichloromethane (120 ml). After 3 hours the reaction is stopped with 1%aqueous solution of sodium bicarbonate (200 ml). Separate the layers. The aqueous layer was extracted with dichloromethane (2 times 50 ml). Organic FR the functions are combined, dried with magnesium sulfate and concentrate under vacuum. It turns out the syrup light orange color. This syrup fray with diethyl ether into a powder. Obtained 6.8 g light korichnego solid tert-butyl-N-[4-(2-phenyl-1H-imidazo[4,5-C]quinoline-5N-oxide with a melting point 178-181°C.

Part G

A solution of tert-butyl N-[4-(2-Hairdryer yl-1H-imidazo[4,5-C]quinoline-5N-oxide (6.8 g, of 15.75 mmol) in dichloromethane (100 ml) cooled in an ice bath. Add concentrated ammonium hydroxide (30 ml). Within 30 minutes in small portions add taillored (3.0 g, of 15.75 mmol).

The reaction mixture is left overnight to warm up to room temperature. The reaction is stopped by the water (350 ml). Separate the layers. The aqueous layer was extracted with dichloromethane (2 times 50 ml). The organic fractions combined, dried with magnesium sulfate and concentrate under vacuum with the formation of solids yellowish-brown color. This substance is purified column chromatography under pressure (silica gel; elution with 10% methanol in dichloromethane). The yield of 4.8 the Bulk of the material is transferred to the next stage. A small portion is recrystallized from toluene, and the obtained solid tert-butyl-N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 182-183°C. Elemental analysis: theory. for C25H29N 5O2: %69,58; %N 6,77; %N 16,22; exp.: %69,86; %N 6,95; %N 15,80.

Part D

The material from Part D was dissolved in methanol (15 ml) and 1N hydrochloric acid (100 ml)and then heated in air for 2 hours, refluxed. The reaction mixture was concentrated under vacuum to a volume of about 50 ml by adding concentrated ammonium hydroxide to pH 12 precipitate is not formed. Using 1N hydrochloric acid, the pH is brought to 7. The mixture is extracted with dichloromethane and then ethyl acetate. The aqueous layer was evaporated to dryness. The residue is dissolved in water (50 ml), and then within 36 hours continuously extracted with boiling chloroform. After evaporation of chloroform extract under vacuum, a solid product is a light brown color. After recrystallization of this product from acetonitrile obtained 2.5 g of 1-(4-amino)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine in the form of a yellowish-white substance with a melting point 175-177°C. Elemental analysis: theory. for C20H21N5: %72,48; %N 6,39; %N 21,13; exp.: %72,72; %N 6,32; %N 20,71.

Part E.

1-(4-Amino)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine (0,331 g, 1.0 mmol) dissolved in anhydrous acetonitrile (35 ml) and the solution cooled to 4°C. is Slowly added a solution of 4-forbindelsesfaneblad (0,194 g, 1.0 mmol) in anhydrous dichloromethane (10 ml). The reaction mixture is left for the weekend slowly heating the change to room temperature. The reaction is stopped by adding a saturated aqueous solution of sodium bicarbonate. The layers are separated and after evaporation of the organic layer receives light yellow solid. This material is recrystallized from isopropyl alcohol and then purified column chromatography under pressure (silica gel; elution with 10% methanol in dichloromethane). Pure fractions are combined and concentrated. After recrystallization of the residue from isopropyl alcohol to obtain 0.2 g of a light yellow solid N-[4-(4-amino-2-phenyl-1 H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-fluoro-1-benzosulfimide with a melting point 214-216°C. Elemental analysis: theory. for C26H24FN5O2S: %S: 63,79; %N 4,94; %N 14,30; exp.: %With: 63,19; %N 4,85; %N 13,90; Mass spectrometry M+1=490,2.

Example 16

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

In accordance with the General method described in Part E of Example 15, 1-(4-amino)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine (0,331 g, 1.0 mmol) interacts with methanesulfonyl anhydride with the formation of white solid N-[4-(4-amino-2-phenyl-1 H-imidazo[4,5-C]quinoline-1-yl)butyl]methanesulfonamide with a melting point 234-235°C. Mass spectrometry M+1=410,2.

Examples 17-33

The compounds presented in the Table below are in accordance with the General method of synthesis is, as described in reaction Scheme II.

1-(2-amino-ethyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (25 mg) was placed in a vial on 2 drachmas (7,4 ml). In turn adds diisopropylethylamine (11 μl, 1.2 equivalent), dichloromethane (1 ml) and sulphonylchloride (1.1 equivalent). 2 hours ampoule is placed in the shaker, and then for 0.5 hour in an ultrasonic camera. The reaction mixture is left overnight at room temperature, and then to confirm the formation of the target product, analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation ghvd (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt need sulfonamida (see tab. 1).

Table 1
Example No.The structure of the free baseExperimentally found molecular weight
17390.2
18460.2
19430.1
20424.1
21504.0

Example No.The structure of the free baseExperimentally found molecular weight
22492.0
23438.1
24534.0
25480.2
26466.2

Example No.The structure of the free baseExperimentally found molecular weight
27454.1
28 438.1
29450.1
30475.1
31474.2

Example No.The structure of the free baseExperimentally found molecular weight
32474.1
33517.2

Example 34

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

This connection receive in accordance with the General procedure described for examples 17-33, except that instead of sulphonylchloride using 1.1 equivalent methanesulfonamido anhydride. (Experimentally found molecular weight=362,2).

Example 35

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

This connection receive in accordance with the General procedure described for examples 17-33, except that, instead of the of sulfonylurea, using 1.1 equivalent triftormetilfullerenov anhydride. (Experimentally found molecular weight=416,1).

Examples 36-40

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

1-(2-Aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (25 mg) was placed in a vial on 2 drachmas (7,4 ml). In turn adds diisopropylethylamine (14 μl, 1.0 equivalent), dichloromethane (1 ml) and sulphonylchloride (1.0 equivalent). 0.5 hours ampoule is placed in the shaker, and during this time, almost everything goes into solution. Later a precipitate. Add a little methanol, and the precipitate dissolves. The reaction mixture for one hour, placed in a shaker, and then for 0.5 hour in an ultrasonic camera. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation ghvd (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography are analyzed by chromium is about-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt need sulfonamida (see table 2).

Table 2
Example No.The structure of the free baseExperimentally found molecular weight
36390.1
37482.1
38418.1
39452.1
40466.1

Examples 41 to 52

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

1-(2-Aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (25 mg) was placed in a vial on 2 drachmas (7,4 ml). In turn adds diisopropylethylamine (14 μl, 1.0 equivalent), dichloromethane (1 ml) and sulphonylchloride (1.0 equivalent). Approximately 60 minutes, the vial was placed in an ultrasonic chamber at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed, and the mod is to cleanse prepreparation HPLC (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt need sulfonamida (see table 3).

Table 3
Example No.The structure of the free baseExperimentally found molecular weight
41502.1
42502.1

Example No.The structure of the free baseExperimentally found molecular weight
43503.2
44458.1
45 494.2
46578.2
47508.3

Example No.The structure of the free baseExperimentally found molecular weight
48520.1
49466.2
50478.2
51418.2
52560.1

Example 53

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

This connection receive in accordance with the General procedure described for examples 41 to 52, except that, instead of sulphonylchloride, using 1.0 equivalent triftormetilfullerenov anhydride. (Experimentally found molecular weight=444,1).

Examples 54-71

The compounds presented in the Table below are in accordance with the General method of synthesis described you the e in reaction Scheme IV.

Part a

A catalytic amount of platinum oxide (IV) was added to a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (2,75 g to 10.8 mmol) in triperoxonane acid (150 ml). The reaction mixture is placed in an atmosphere of hydrogen under a pressure of 50 pounds per square inch (3,44×105PA). Conducted after 1 week mass spectrometric analysis shows the presence in the reaction mixture as a starting material, and tetrahydroindole product. To the reaction mixture add fresh catalyst and continue to hydrogenation at 50 psi (3,44×105PA). After 2 weeks in order to remove the catalyst, the mixture is filtered. The filtrate is concentrated under vacuum. The residue is dissolved in 1N hydrochloric acid (120 ml), and within 1 hour, stirred solution at room temperature. The solution russulaceae 50%sodium hydroxide to pH 10 and extracted with dichloromethane (5 times 100 ml). The extracts are combined and concentrated under vacuum. Output: 2,08 g white solid 1-(4-aminobutyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine.

Part B

1-(2-Aminobutyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine (25 mg) was placed in a vial on 2 drachmas (7,4 ml). In turn adds diisopropylethylamine (11 μl, 1.2 equivalent), dichloromethane (1 ml) and sulphonylchloride (1.1 equivalent). About 6 hours ampoule is placed in the shaker. The reactions is nnow the mixture is left overnight at room temperature and for to confirm the formation of the target product, analyze it on chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt need sulfonamida (see table 4).

Table 4
Example No.The structure of the free baseExperimentally found molecular weight
54366.2
55366.1
56436.2

Example No.The structure of the free baseExperimentally naide the Naya molecular weight
57406.1
58400.1
59434.0
60468.0

Example No.The structure of the free baseExperimentally found molecular weight
61526.0
62456.1
63442
64414

Example No.The structure of the free baseExperimentally found molecular weight
65430
66508.0
67414.1
68 426.1

Example No.The structure of the free baseExperimentally found molecular weight
69451.1
70450.1
71493.1

Example 72

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

This connection receive in accordance with the General procedure described for examples 54-71, except that, instead of sulphonylchloride, using 1.1 equivalent methanesulfonamido anhydride. (Experimentally found molecular weight=338,2).

Examples 73-201

The compounds presented in the Table below are in accordance with the method described above in reaction Scheme II, using the following General methods.

1H-Imidazo[4,5-C]quinoline-4-amine (50 mg) was placed in a vial on 2 drachmas (7,4 ml). Add diisopropylethylamine (1.2 equivalents) in dichloromethane (1 ml). Add the solution containing sulphonylchloride (1.1 equivalent) in dichloromethane (~1 ml). For about 2-16 hours (about the commonly 2 hours), the ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column Capcell Cancer C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt need sulfonamida (see table 5).

530.1
Table 5
Example No.The structure of the free baseMass spectrometry (head) m/e
73526.2
74432.2
75600.3
76578.2
77

Example No.The structure of the free baseMass spectrometry (head) m/e
78530, 532.0
79565.0
80520.1
81512.1
82452.1

Example No.The structure of the free baseMass spectrometry (head) m/e
83497.1
84496.1
85536.1
86531.0, 533.0
87470.1

Example No.The structure of the free base Mass spectrometry (head) m/e
88497.1
89526.2
90542.0
91536.1
92520.0, 522.0

Example No.The structure of the free baseMass spectrometry (head) m/e
93488.1
94471.1
95470.1
96528.1
97511.1

Example No.The structure of the free baseMass spectrometry (head) m/e
98508.1
99 537.9
100516.0, 518.0
101492.0, 494.0
102603.1

Example No.The structure of the free baseMass spectrometry (head) m/e
103520.1
104482.1
105Us $ 560.0, 562
106484.1
107522.1

Example No.The structure of the free baseMass spectrometry (head) m/e
108364.1
109432.0
11051.1
111392.2
112460.1

Example No.The structure of the free baseMass spectrometry (head) m/e
113468.2
114547.3
115406.1
116420.1

Example No.The structure of the free baseMass spectrometry (head) m/e
117434.1
118454.1
119468.1
120472.1

Example No.The structure of the free baseMA is with spectrometry (head) m/e
121472.1
122472.1
123473.1
124484.1

Example No.The structure of the free baseMass spectrometry (head) m/e
125484.1
126488.1
127488.1
128488.0

Example No.The structure of the free baseMass spectrometry (head) m/e
129490.1
130490.1
131494.0
132 496.2

Example No.The structure of the free baseMass spectrometry (head) m/e
133496.1
134496.2
135499.1
136499.1

Example No.The structure of the free baseMass spectrometry (head) m/e
137508.1
138513.1
139514.1
140514.1

Example No.The structure of the free baseMass spectrometry (head) m/e
141518.0
142 522.1
143522.0, 524.0
144522.0, 524.0

Example No.The structure of the free baseMass spectrometry (head) m/e
145522.0, 524.0
146522.0, 524.0
147522.0, 524.0
148528.2

Example No.The structure of the free baseMass spectrometry (head) m/e
149528.0, 530.0
150528.0, 530.0
151532, 534.0
152532, 534.0

Example No. The structure of the free baseMass spectrometry (head) m/e
153538.1
154538.1
155538, 540.0
156580.0

Example No.The structure of the free baseMass spectrometry (head) m/e
157605.1
158454.2
159468.2
160479.2

Example No.The structure of the free baseMass spectrometry (head) m/e
161532.2
162479.1
163 486.1
164490.2

Example No.The structure of the free baseMass spectrometry (head) m/e
165498.1
166498.1
167502.1
168502.1

Example No.The structure of the free baseMass spectrometry (head) m/e
169504.2
170504.1
171505.2
172506.1

Example No.The structure of the free baseMass spectrometry (head) m/e
173 506.2
174506.2
175510.3
176510.2

Example No.The structure of the free baseMass spectrometry (head) m/e
177513.2
178513.2
179513.2
180524.2

Example No.The structure of the free baseMass spectrometry (head) m/e
181526.2
182530.2
183532.2
184534.1

Example No.The structure of the free baseMass spectrometry (head) m/e
185533.1
186536.1, 538.1
187544.1
188546.3

Example No.The structure of the free baseMass spectrometry (head) m/e
189556, 558.1
190556, 558.1
191556, 558.1
192562, 564.1

Example No.The structure of the free baseMass spectrometry (head) m/e
193567.2
194580.3
195593.2
196606.0, 608.0, 609.9

Example No.The structure of the free baseMass spectrometry (head) m/e
197610.0, 612.0, 614.0
198616, 618.1
199616.0, 617.9, 620.0
200528.3

Example No.The structure of the free baseMass spectrometry (head) m/e
201522.2

Examples 202-213

The compounds presented in the Table below are in accordance with the General method of synthesis described above in reaction Scheme VI.

Part a

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

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

Part B

Using the methods described for examples 73-201, tetrahydroisoquinoline part of And interact with the corresponding sulphonylchloride with the formation of the desired sulfonamida (see table 6).

Table 6
Example No.The structure of the free baseMass spectrometry (head) m/e
202394.20
203422.1
204462.1
205470.1

Example No.The structure of the free baseMass spectrometry (head) m/e
206549.2
207410.2
208424.2
209438.2

Example No.The structure of the free baseMass spectrometry (head) m/e
210458.1
211472.2
212532.2
213551.2

Example 214

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

This connection receive in accordance with the methods described for examples 202-213, except that instead of sulphonylchloride use methanesulfonyl anhydride.

Example 215

N-[4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N-methyl-3,5-dimethylisoxazole-4-sulfonamidemetformin

Part a

In accordance with the General method of example DC001, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine interacts with a 3.5-dimethyloxazole-4-sulphonylchloride with the formation of N-[4-(4-Amino-2-(2-metakit the l)-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N-methyl-3,5-dimethylisoxazole-4-sulfonamida of triptoreline.

Part B

Sodium hydride (5.8 mg) was added to a solution of material from part a (to 25.4 mg) in dimethylformamide. To the reaction mixture add iodomethane (3,2 μl) and shaken for 2 hours the reaction mixture at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column Capcell Cancer C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Liofilizovannye material a second time clean prepreparation HPLC under the same conditions except that a gradient elution from 5% to 95% B is not for 10 minutes, and 60 minutes. Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired amide.

Example 216

N-[4-(4-Amino-2-(2-IU the oxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N-methyltrifluoroacetamide

This connection receive in accordance with the General procedure described above in example 215, except that instead of sulphonylchloride in part a use triftormetilfullerenov anhydride.

Examples 217-221

The compounds in the examples presented in the table below are in accordance with the following General method.

1 N-Imidazo[4,5-C]quinoline-4-amine or 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine (50 mg) was placed in a vial on 2 drachmas (7,4 ml). Add dichloromethane (2 ml) and diisopropylethylamine (1.2 equivalent). Add dimethylsulphamoyl (1.1 equivalent). Approximately 2-4 hours ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation ghvd (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions with the United by and lyophilized. Formed trifurcata salt of the desired sulphonamide (see table 7).

Table 7
Example No.The structure of the free baseMass spectrometry (head) m/e
217393.1
218421.2
219483.3
220423.2

Example No.The structure of the free baseMass spectrometry (head) m/e
221425.1

Examples 222-228

The compounds presented in the Table below are in accordance with the General method of synthesis described above in reaction Scheme V.

1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (50 mg) was placed in a vial on 2 drachmas (7,4 ml). Added 4-(dimethylamino)pyridine (19 mg, 1.0 equivalent) in dichloromethane (800 ml). The ampoule is sealed and cooled to -78°in a bath of dry ice / acetone. Add sulfurylchloride (186 μl of 1M solution in dichlo the methane). About 30 minutes the vial was placed in a shaker, and then again cooled to -78°C. In a separate vial load amine of General formula R4R5NN (2.0 equivalent), triethylamine (2.0 equivalents) and dichloromethane (1 ml) and cooled to -78°C. a Solution of amine / triethylamine are added to the first vial. About 1 hour ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation ghvd (column, Capcell Pak C18, 35 mm×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired sulphonamide (see table 8).

Table 8
Example No.The structure of the free baseMass spectrometry (head) m/e
222 449.2
223475.3
224469.1
225490.2

226497.1
227533.2
228479.1

Examples 229-231

The compounds presented in the Table below are in accordance with the method described in the examples 222-228, except that the amine of General formula R4R5NH interacts with sulfurylchloride with the formation of intermediate sulfhemoglobin, which then reacts with 2 equivalents of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (see table).

Table 9
Example No.The structure of the free baseMass spectrometry (head) m/e
229447.1
230 449.2
231483.2

INDUCTION of CYTOKINES IN HUMAN CELLS

To study the induction of cytokines, compounds of the present invention was used, the system of human blood cells in vitro. The method is based on measuring the level (s) of interferon and tumor necrosis factor (IFN and TNF, respectively)secreted into the culture medium, as described by Testerman, etc (Testerman et al., "Cytokine induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995))

Preparation of blood cells for culture

Whole blood taken from a vein of a healthy person and placed in a test tube. Mononuclear cells from peripheral blood (MCPC) was isolated from whole blood in the density gradient by centrifugation with the use of device Histipaque®-1077 (F. Sigma Chemicals, St.Louis, MO). Mononuclear cells peripheral blood are suspended at a concentration of 3-4×106cells/ml in RPMI medium 1640 containing 10% fetal bovine serum, 2 mm L-glutamine and 1% of a mixture of penicillin and streptomycin (complete RPMI medium). Suspension MCPC make a 48-hole flat-bottomed sterile tablets for tissue culture (F. Costar, Cambridge, MA, or F. Becton Dickinson Labware, Lincoln Park, NJ), in which there are an equal volume of complete RPMI medium containing the test drug.

<> Preparation

The drug solubilizer in dimethyl sulfoxide (DMSO). The final concentration of DMSO to be added to the culture wells should not exceed 1%.

Incubation

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

Selection

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

The analysis of TYPHUS (ELISA) for maintenance α-interferon is α -tumor necrosis factor.

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

Concentration α-tumor necrosis factor determined using a kit from TYPHOID F. Genzyme, Cambridge, MA; F. R&D Systems, Minneapolis, MN; or F. Pharmigen, San Diego, CA)

The table below shows found the lowest concentration of each drug for the induction of tumor necrosis factor. “**” - reflects the lack of induction in any of the tested concentrations(0,12, 0,37, 1,11, 3,33, 10 and 30 µm); “***” - reflects the lack of induction in any of the tested concentrations(0,0001, 0,001, 0,01, 0,1, 1 and 10 μm) (see table 10).

Table 10
Induction of cytokines in human cells
Room

example
The lowest effective concentration (µm)
InterferonThe tumor necrosis factor
10,123,33
2****
30,01**
60,000171,11
70,01**
90,04
110,011,11
1310**
171,113,33
183,33**
190,123,33
200,123,33
211,1130
220,37**
230,1210
240,1230
253,33**
2610**
271,1130
281,1130
290,3710
301,11**
311,11**

3,33
321,11**
331,1110
340,040,37
351,1110
360,00153,33
370,011,11
380,015 0,37
400,00153,33
410,01**
420,01**
430,04**
440,00151,11
450,37**
460,37**
470,37**
480,3710
500,12**
510,00150,37
520,1210
530,013,33
5410**
553,33**
56****
573,33**
583,33**
593,33**
60****
613,33**
62****
63****
643,33**
65**
66**30
6710**
6810**
6910**
70****
71**30
723,33**
730,0010,1
740,0010,01
75******
76******
770,0011
780,0010,1
790,011
80110
810,0011
820,0011
830,0011
84110
851***
860,011
870,0011

880,011
89 0,0011
900,011
910,011
920,110
930,0010,1
940,0011
950,0011
961***
970,110
981***
990,110
1000,0110
1010,0110
1020,00110
1030,110
1040,01***
105110
10611
1071***
1080,110
109110
11010***
1110,00110
1120,0001***
1130,0001***
11 0,01***
1160,0011
1170,00011
1200,00011
1210,000110
1220,00011
1230,000110
1270,000110
1280,00011
1310,00011
1380,000110
1480,00011
1520,000110
1540,00110
1580,00011
1590,00010,1
1600,0011
1610,0110
1840,00011
2000,010,1
2020,00011
2030,00011
2040,00011
2050,00011
2061 ***
2070,0011
2080,00011
2090,00010,1

2100,00011
2110,00011
2120,00010,01
2130,00011
2140,0110
2150,011
2171***
2180,00011
2200,00011
2210,00011
2240,000110
2260,00010,1
2270,001***
2290,00010,1
2300,00011
2310,00011

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

1. The compound of formula (I)

where

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

R1is-alkyl-NR3-SO2-X-R4;

X is a bond or-NR5-;

R4is phenyl, naphthyl, thienyl, chinoline, ethenolysis; tetrahydroquinolines, thiazolyl, oxazolyl, pyrazolyl, piperazinil, piperidinyl, thiomorpholine, pyrrolidine, alkyl or alkenyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

is phenyl, substituted NO2;

- O-alkyl;

- COOH;

- CO-O-alkyl;

- S(O)0-2-alkyl;

- (alkyl)0-1-NR3R3;

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

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

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

- halogen;/p>

- halogenated;

- halogenoalkanes;

- CO-halogenoalkanes;

- NO2;

- CN; and in the case of alkyl, oxoprop;

R2is selected from the group which consists of:

is hydrogen;

- alkyl;

is phenyl;

- alkyl-O-alkyl; and

- alkyl, substituted by one or more substituents chosen from:

is phenyl, substituted by alkoxyl;

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

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

n is the number 0,

or its pharmaceutically acceptable salt.

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

3. The compound according to claim 2, wherein R3is hydrogen.

4. The compound according to claim 2, wherein R1is -(CH2)2-4-NR3-SO2-R4.

5. The compound according to claim 2, wherein R4is selected from the group comprising phenyl, naphthyl, thienyl, chinoline, ethenolysis; thiazolyl, oxazolyl, pyrazolyl, piperazinil, piperidinyl, thiomorpholine, pyrrolidine and alkyl, each of which can be unsubstituted or substituted od is them or more substituents, selected from the group which consists of:

- alkyl;

is phenyl;

is phenyl, substituted NO2;

- O-alkyl;

- COOH;

- CO-O-alkyl;

- S(O)0-2-alkyl;

- (alkyl)0-1-NR3R3;

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

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

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

- halogen;

- halogenated;

- halogenoalkanes;

- CO-halogenoalkanes;

- NO2;

- CN; and in the case of alkyl, oxoprop;

6. The compound according to claim 2, wherein R2is selected from the group comprising hydrogen; alkyl With1-4; alkyl (C1-4-O-alkyl, C1-4.

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

8. The compound according to claim 1, wherein X is-NR5-.

9. The connection of claim 8, wherein R1is -(CH2)2-4-NR3-SO2-NR5-R4.

10. The connection of claim 8, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; alkyl (C1-4-O-alkyl, C1-4.

11. The connection of claim 8, wherein R4and R5together form a substituted or unsubstituted pyrolidine, thiomorpholine, piperidine or pieperazinove ring in the possibility of substitution by alkyl or C(O)-O-alkyl.

12. Connection claim 11, wherein R3is hydrogen.

13. Connection claim 11, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; alkyl (C1-4-O-alkyl, C1-4.

14. The connection of claim 8, wherein R4and R5is alkali.

15. The connection 14, wherein R3is hydrogen.

16. The connection 14, wherein R2is selected from the group comprising hydrogen; alkyl; and (C1-4alkyl-O-C1-4-alkyl.

17. The connection of claim 8, wherein R3is hydrogen.

18. Compound selected from the group which consists of:

N2-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-2-thiophenesulfonyl;

N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-1-benzosulfimide;

N8-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-8-chinaincorporated;

N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-5-(dimethylamino)-1-naphthalenesulfonate;

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

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-1-benzosulfimide;

N8-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-8-chinaincorporated;

N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-is)butyl]-2-thiophenesulfonyl;

N2-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-2-thiophenesulfonyl;

N1-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-1-benzosulfimide;

N8-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-8-chinaincorporated;

N1-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate;

N1-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-4-fluoro-1-benzosulfimide;

N1-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-fluoro-1-benzosulfimide;

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

N2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-1-yl]ethyl}-2-thiophenesulfonyl;

N1-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-1-yl]ethyl}-1-naphthalenesulfonate;

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

N2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-2-thiophenesulfonyl;

N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-5-(dimethylamino)-1-naphthalenesulfonate;

N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-4-fluoro-1-benzosulfimide;

N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-3-fluoro-1 be solarpanel;

N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-1-benzosulfimide;

N8-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-8-chinaincorporated;

N2-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-8-thiophenesulfonyl;

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

N2-[4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-2-thiophenesulfonyl;

N1-[4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate;

N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-1-benzosulfimide;

N1-{4-[4-amino-2-(methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-5-(dimethylamino)-1-naphthalenesulfonate;

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

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

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

N'-[4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-N,N-dimethylacetamide;

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

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

N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-1-pyrrolidinecarbonyl;

N1-[4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-fluoro-1-benzosulfimide;

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

19. Compound selected from the group which consists of:

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate;

N1-[4-(4-amino-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonate;

N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-2-thiophenesulfonyl;

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

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-1-benzosulfimide;

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-3-nitro-1-benzosulfimide;

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-3-amino-1-benzosulfimide;

N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-4-nitro-1-benzosulfimide;

N1 -[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-amino-1-benzosulfimide;

N5-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-5-ethynodiolthinyl;

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

N1-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-1-butanesulfonate;

N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-fluoro-1-benzosulfimide;

N1-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-4-fluoro-1-benzosulfimide; and

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

20. Pharmaceutical drug for the induction of interferon-α or α-tumor necrosis factor comprising a therapeutically effective amount of a compound according to claim 1 or 2, or 8 and a pharmaceutically acceptable carrier.

21. Method of induction of the biosynthesis of cytokines in animals, including the introduction of the animal a therapeutically effective amount of a compound according to claim 1 or 2, or 8.

22. A method of treating viral diseases in animals, including the introduction of the animal a therapeutically effective amount of a compound according to claim 1 or 2, or 8.

23. The method of treatment neoplasticeskih pathologies in animals, including the introduction of the animal a therapeutically effective amount the VA compound according to claim 1, or 2, or 8.

Priority from 10.06.1999

The points 1, 2, 3, 5, 6, 8, 10, 14, 15, 16, 17, 20, 21, 22, 23 if the radical R4represents phenyl; -O-alkyl; -CO-O-alkyl; -S(O)0-2-alkyl; oxoprop; halogen; NO2; and the radical R2selected from the group comprising: hydrogen; -alkyl; -phenyl; and according to claim 19 where the compound is N1-[4-(amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-1-butanesulfonic.

From 07.06.2000

The points 1, 2, 3, 5, 6, 8, 10, 14, 15, 16, 17, 20, 21, 22, 23 for all other values of these radicals and other signs and items 4; 7; 9; 11; 12; 13; 18.



 

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