Arylether-substituted imidazoquinolines, pharmaceutical compositions based on the same, methods for treatment of viral diseases based on the same and methods for treatment of tumor disease based on the same

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to arylether-substituted imidazoquinolines and tetrahydroimidazoquinolines useful in inducing of cytokines biosynthesis. In particular described are imidazoquinolines of formula I wherein X represents -CHR3; R1 represents aryl, R4-aryl; R2 represents hydrogen atom, alkyl, aryl, tetrahydrofuran; alkyl-Y-alkyl; alkyl-Y-aryl, and alkyl substituted with one or more substituents; R are independently C1-C10-alkyl, C1-C10- alkoxy, hydroxyl group; halogen atom, and trifluoromethyl or pharmaceutically acceptable salts thereof; meanings of the rest substituents are as defined in description. Also disclosed are pharmaceutical compositions for inducing of cytokines biosynthesis, methods for treatment of viral and tumor diseases.

EFFECT: new compounds with value biological properties.

39 cl, 8 tbl, 146 ex

 

This invention relates to imidazoquinolines compounds that are essential and aryl or alkenylphenol functional group in position 1, as well as to pharmaceutical compositions containing such compounds. An additional aspect of this invention refers to the use of the above compounds as immunomodulators, for stimulation of cytokine biosynthesis in an animal's body, as well as for the treatment of various diseases including viral and neoplastic diseases.

The first reliable data on 1H-imidazol[4,5-C]quinoline cyclic system of the present Bukhmanom with TCS. in the journal J. Orq. Chem.. 15, 1278-1284 (1950), who reported the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline with a view to its possible use as antimalarials. Subsequently there were reports about the synthesis of different substituted 1H-imidazo[4,5-C]quinoline. For example, with Jain al., J. Med. Chem. 11, 87-92 (1968), synthesized 1-[2-4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline for its use as a possible anti-seizure drugs and cardiovascular drugs. In addition, Baranov al., Chem. Abs. 85, 94362 (1976)reported the synthesis of several 2-accomidate[4,5-C]quinoline, and Bereni with al., J. Heterocyclic Chem 18, 1537-1540 (1981)also reported the synthesis of several 2-accomidate[4,5-C]quinoline.

It was later revealed that some of the known 1H-imidazo[4,5-C]quinoline-4-amines and their 1 - and 2-substituted derivatives can be used as antiviral agents bronchodilators and immunomodulators. These compounds are described, among other chemical products in the U.S. patents№№4689338, 4698348, 4929624, 5037986, 5268376, 5346905 and 5389640; all of these patents are listed in the list of references.

Of great interest to imidazoquinolines cyclic systems does not stop and present. Known to some 1H-imidazo[4,5-C]naphthiridine-4-amines and 1H-imidazo[4,5-C]pyridine-4-amines and 1H-imidazo[4,5-C]quinoline-4-amines having the ether group containing a substituent in position 1. These compounds are described in U.S. patent No. 5268376, 5389640, 5494916, as well as in WO 99/29693.

Currently, there is a need for compounds which are able to modulate the immune response through stimulation of cytokine biosynthesis or other mechanisms.

Summary of the invention

Found a new class of compounds able to stimulate cytokine biosynthesis in animals. Accordingly, the invention provides compounds of imidazo[4,5-C]quinoline-4-amine, tetrahydroimidazo[4,5-C]quinoline-4-amine, which contain a Deputy with the ether group in the 1-position. According to the IR spectroscopy of these compounds have the formula (I), (II), (III) and (IV). Below is a General structural formula of these compounds

and nature will replace the lei X, R1, R2and R is defined below for each class of compounds having the formula (I), (II), (III) and (IV).

Compounds having General formula (I), (II), (III) and (IV)are useful immune response modifiers due to their ability to stimulate cytokine biosynthesis otherwise modulate the immune response when introduced into the animal organism. This makes the above compounds are useful tools for the treatment of various diseases, such as viral infections and neoplastic diseases that cause such a change in the immune response.

The invention also provides pharmaceutical compositions containing compounds that modify the immune response, and reports on ways to stimulate cytokine biosynthesis in an animal, treating a viral infection and/or neoplastic disease in an animal by introducing into the body of the compounds of formula (I), (II), (III) and (IV).

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

Detailed description of the invention

As mentioned above, we found some compounds that stimulate the biosynthesis of cytokines and thereby modify the immune response in animals. Such compounds have the General formula (I), (II), (III) and (IV), are shown in the below.

Proposed in the invention imidazoquinolines compounds containing ether and aryl or alkenylphenol functional group in position 1, have the formula (1):

where X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

R1selected from the group including:

alkenyl;

- aryl;

- R4-aryl;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

each R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O-groups;

each R3represents independently from each other hydrogen or C1-10alkyl group;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n can change the I from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

In the present invention are also imidazoquinolines compounds containing ester group in position 1, and the Deputy with the ether group contains also alkylamino group. These compounds have the General structural formula (II):

where

X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R10selected from the group including:

- the hydrogen atom

- alkyl;

alkenyl; and

- aryl;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

the value of n is in the interval is from 0 to 4;

each group of Y is independently from each other represents-O - or S(O)0-2-;

each R3represents independently from each other hydrogen or C1-10alkyl group; and

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

The present invention also includes tetrahydroisoquinoline compounds containing ether and aryl or alkenylphenol group in position 1. Such tetrahydroisoquinoline compounds have the formula (III):

where X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl; and

- R4-aryl;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-aryl;

- alkyl-Y-alkenyl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-is 1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each R3represents independently from each other hydrogen or C1-10alkyl group;

each group of Y is independently from each other represents-O - S(O)0-2-;

the value of n can vary from 0 to 4; and

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

Additional class presented in this invention, compounds modifying the immune response, are compounds, including firstarray Deputy located in position 1, and this firstarray Deputy also contains alkylamino group. These compounds have the General structural formula (IV):

where

X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R10selected from the group including:

- the hydrogen atom

- alkyl;

alkenyl; and

- aryl;

R2 selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-aryl;

- alkyl-Y-alkenyl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

each R3represents independently from each other hydrogen or C1-10alkyl group;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n ranges from 0 to 4; and

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

Getting connections

Proposed in the invention compounds can be obtained in accordance with the following scheme I, the reaction in which the values of R, R2, X and n are defined above, and the substituent R11represents an alkyl group, aryl Deputy, and the aryl group may b the th unsubstituted or substituted, or R11is a substituted aryl group, provided that when R11is a substituted aryl group, at least one Deputy is a strong electron-acceptor group, located in the ortho - or para-position relative to the ether link.

In accordance with scheme I, the reaction of 4-amino-1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula X is subjected to alkylation under the action of a halide of formula XI, resulting in a 1H-imidazo[4,5-C]quinoline-4-amine of formula XII, which is a derivative of the compound I. product Alcohol of formula X is treated with sodium hydride, dispersed in a suitable solvent such as N,N-dimethylformamide, and the result is the corresponding alkoxide. Then to the reaction mixture add the corresponding halide and the mixture is incubated at ambient temperature or optionally at a low heat (about 50°). Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

There are many known compounds of formula X, see, for example, Gerster, U.S. Patent No. 4689338 and Gerster with al., U.S. patent No. 5605899, and cited in these patents. Other compounds of this type can easily be obtained by known methods Shin is ESA, see, for example, with Andre al. U.S. patent No. 5578727; Gerster, U.S. Patent No. 5175296, Nicolaides with al., U.S. patent No. 5395937 and Gerster with al., U.S. patent No. 5741908 and cited in these patent literature. Many halides of the formula XI are commercial products; others can be easily synthesized by known methods.

Proposed in the invention compounds can be obtained in accordance with reaction scheme II, in which the values of R, R2, R11, X and n are defined above.

At the stage (1) process (reaction scheme II) 1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XIII is subjected to alkylation under the action of a halide of formula XI, resulting in a 1H-imidazo[4,5-C]quinoline-1-silt ether of the formula XIV. To obtain alkoxide alcohol XIII is treated with sodium hydride, dispersed in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran. To the resulting alkoxide add the halide. An alternative method consists in carrying out the reaction between the alcohol and halide in a two-phase mixture consisting of 50%aqueous sodium hydroxide solution and an inert solvent, such as dichloromethane, in the presence of a phase transfer catalyst, such as designed chloride. The reaction can be conducted at ambient temperature. Many of the compounds of formula XIII are known, see, for example, Gerster, U.S. patent No. 4689338, other compounds of this type can be easily obtained by known synthetic methods, see, for example, Gerster with al., U.S. patent No. 5605899 and Gerster with al., U.S. patent No. 5175296.

At stage (2) process (reaction scheme II) 1H-imidazo[4,5-C]quinoline-1-silt ester of formula XIV under the action of a conventional oxidizing agent capable of forming N-oxide, oxidized till 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XV. Mainly a solution of the compounds of formula XIV in a suitable solvent, such as chloroform or dichloromethane, are oxidized at ambient temperature under the action of 3-chloroperoxybenzoic acid.

At stage (3) process (reaction scheme II) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XV miniroot to 1H-imidazo[4,5-C]quinoline-4-amine of formula XII, which is derived by connecting the product of stage I. (3) includes (i) the reaction accession XV to atsiliruyuscimi agent and (ii) the interaction of the formed product with aminimum agent. Part (i) stage (3) is in the interaction of the N-oxide of formula XV with allermuir agent. Suitable allerease agents are alkyl - or arylsulfonate (for example, benzosulphochloride, methanesulfonate, p-toluenesulfonate). Preferred allerease agents are arylsulfonamides, with the most preferred alli the ith agent is para-toluenesulfonate. In part (ii) stage (3) the product obtained in part (i), treated with excess amineralo agent. Suitable ominiruyuschim agents are ammonia (e.g. ammonium hydroxide) and ammonium salts (e.g. ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is the preferred aminimum agent. The reaction is mainly carried out by dissolving the N-oxide of formula XV in an inert solvent, such as dichloromethane, adding to the resulting solution miniraise agent and then slowly adding allerease agent. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

An alternative way to carry out stage (3), (i) processing the N-oxide of formula XV with isocyanate and (ii) subjecting the resulting product to hydrolysis. Part (i) is in the interaction of the N-oxide XV with an isocyanate in which the isocyanate group is linked to a carbonyl group. The preferred isocyanates are trichlorotriazine and abolitionary, such as benzoylation. The reaction between the isocyanate and N-oxide is carried out in anhydrous conditions, by adding the isocyanate to a solution of N-oxide in an inert solvent, such as chloroform or dichloromethane. Part (ii) is to conduct hydrolysis product formed in part (i). The hydrolysis can is rowedit using conventional methods, such as heating in the presence of water or lower alcohols, preferably in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

The compounds of formula I in which R, R2, X and n are defined above, and the substituent R1represents a substituted phenyl group can be obtained according to reaction scheme III. In this scheme, the value of m ranges from 0 to 3, and each substituent R' is independently selected from the group consisting of the following groups: alkyl-, alkoxy-, alkylthio, keloidalis, calidolactis, haloidalkyls-, halogen atom, nitro-, mercapto-, cyano-, carboxy-, formyl-, aryl-, aryloxy, aaltio, Allakaket, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatics, heteroskedascity-, amino-, alkylamino-, dialkylamino-, heterocyclyl, heteroseksualci, alkylsulphonyl, alkenylboronic, arylcarbamoyl, alkoxycarbonyl, haloidohydrocarbons, calidolactis, alkylthiomethyl, aryloxyalkyl, alkanoyloxy, alkanity, alkanolamine, urologic and aroylamino-.

In accordance with scheme III, the reaction of 4-amino-1H-imidazo[4,5-C]quinoline-1-silt the Peart formula X is subjected to condensation with a phenol of the formula XVI, resulting gain 1H-imidazo[4,5-C]quinoline-4-amine of formula XVII, which is derived by the coupling of the product of formula I. Preferably the solution of the compounds of formula X and phenol in an appropriate solvent, such as N,N-dimethylformamide, at ambient temperature is treated with diethylazodicarboxylate and triphenylphosphine. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained in accordance with scheme IV reaction, in which the values of R, R2, R11, X and n are defined above.

At the stage (1) process (scheme IV reaction) hydroxyl group, 1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XIII protect benzyl group. The alcohol of formula XIII is treated with sodium hydride, dispersed in a suitable solvent such as N,N-dimethylformamide, and receive the corresponding alkoxide. This alkoxide is subjected to alkylation under the action of benzylbromide and the result is a compound of formula XVIII. The reaction can be conducted at ambient temperature.

At stage (2) process (scheme IV reaction), the compound of formula XVIII using the method used in stage (2) process (reaction scheme II), to oxidize 1H-imidazo[4,5-C]quinoline-5N-oxide of formula IX.

At stage (3) process (scheme IV reaction) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XIX glorious and the result is 4-chloro-1H-imidazo[4,5-C]quinoline of formula XX. Preferably a solution of the compounds of formula XIX in a suitable solvent, such as toluene, is treated at ambient temperature with phosphorus oxychloride.

At stage (4) process (scheme IV reaction) 4-chloro-1H-imidazo[4,5-C]quinoline of formula XX is treated with phenol and receive a 4-phenoxy-1H-imidazo[4,5-C]quinoline of formula XXI. First, the phenol to obtain phenoxide treated with sodium hydride, dispersed in an appropriate solvent, such as diglyme. Then phenoxide at elevated temperature is treated with a compound of formula XX.

At stage (5) process (scheme IV reaction) from compounds of formula XXI remove the protective benzyl group and receive a 4-phenoxy-1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XXII. The reaction is preferably carried out at ambient temperature, slowly adding cryptometrics acid to a solution of the compounds of formula XXI in an appropriate solvent, such as dichloromethane.

At stage (6) process (scheme IV reaction) 4 phenoxy-1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XXII is subjected to alkylation under the action of a halide Hal-R11and the result is 4 phenoxy-1H-imidazo[4,5-C]quinoline-1-silt ether of the formula XXIII. And coxed the compounds of formula XXII get in the presence of a catalyst transfer phases, such as benzyltrimethylammonium, adding alcohol to the two-phase system consisting of a 50%aqueous solution of sodium hydroxide and an inert solvent, such as dichloromethane. This is followed by alkylation of the alkoxide. The reaction can be conducted at ambient temperature.

At stage (7) process (scheme IV reaction) 4 phenoxy-1H-imidazo[4,5-C]quinoline-1-silt ether of the formula XXIII are aminating and get 1H-imidazo[4,5-C]quinoline-4-amine of formula XII, which is derived by the coupling of the product of formula I. For carrying out this reaction, the compound of formula XXIII is mixed with ammonium acetate and the mixture is heated at a temperature of about 150°C. a Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention tetrahydroisoquinoline can be obtained according to scheme V the reaction, in which the values of R, R2, R11, X and n are defined above.

According to scheme V the reaction of 4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XXIV alkylate using halide XI to 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of formula XXV, which is derived by the coupling of the product of formula III. To obtain alkoxide of the alcohol of formula XXIV are processed is t sodium hydride, dispersed in an appropriate solvent, such as N,N-dimethylformamide. Then, the alkoxide is combined with the halide, and the reaction is carried out at ambient temperature. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

There are many known tetrahydro-1H-imidazo[4,5-C]quinoline of formula XXIV, see, for example, Nicolaides with al., U.S. patent No. 5352784; other similar compounds can be obtained by known synthetic methods, see, for example Lindstrom, U.S. Patent No. 5693811 quoted in it literature.

Proposed in the invention compounds can be obtained according to scheme VI reaction, in which the values of R, R1, R2, X and n are defined above.

At the stage (1) process (scheme VI reaction of 4-chloro-3-nitroquinoline formula XXVI is treated with the amine of formula R1-O-X-NH2to obtain 3-nitroanilin-4-amine of formula XXVII. The reaction is carried out by adding the amine to a solution of the compounds of formula XXVI in an appropriate solvent, such as chloroform or dichloromethane; in some cases, the reaction is carried out under heating. Aware of many of the quinoline of formula XXVI (see, for example, U.S. Patent No. 4689338 and cited in the literature it).

At stage (2) process (scheme VI reaction of 3-nitroanilin-4-amine of formula XXVII to restore China is n-3,4-diamine of formula XXVIII. Preferably, the recovery is carried out using a conventional heterogeneous hydrogenation catalyst, such as deposited on activated carbon, palladium or deposited on activated carbon, platinum. The reaction typically can be performed in a Parr apparatus in a suitable solvent, such as isopropyl alcohol or, preferably, toluene.

At stage (3) process (scheme VI reaction) quinoline-3,4-diamine of formula XXVIII is treated with a carboxylic acid or equivalent connection and get 1H-imidazo[4,5-C]quinoline of formula XXIX. Suitable equivalents of carboxylic acid are difficult orthoepy and 1,1-diakoniekrankenhaus. Carboxylic acid or equivalent is chosen so that they provide an introduction to the compound of formula XXIX desired substituent R2. For example, when used for this purpose triethylorthoformate in the reaction will be obtained compound in which R2represents a hydrogen atom, and when using triethylorthoformate - R2will be a group of CH3. The reaction can be carried out in the absence of solvent or in an inert solvent, such as toluene. The reaction is carried out under sufficient heat to ensure the removal of any alcohol or water formed during the reaction as by-products. On desire is human reaction can be carried out in the presence of a catalyst, such as hydrochloric acid pyridine.

Alternatively, stage (3) can be performed when (i) the interaction of the diamine of formula XXVIII with allelochemical formula R2C(O)Cl and (ii) subsequent cyclization of the resulting product. In part (i) allalone added to a solution of the diamine in a suitable solvent, such as acetonitrile, pyridine or dichloromethane. The reaction can be conducted at ambient temperature. In part (ii) the product obtained in part (i), is heated in pyridine in the presence of a base. Preferably the product obtained in part (i)is refluxed in ethanol in the presence of excess triethylamine or heated with methanolic ammonia solution. Alternatively, if part (i) is carried out in pyridine, part (ii) after conducting the analysis, which shows that the reaction in part (i) is fully completed, can be performed simply by heating the reaction mixture.

At stage (4) process (scheme VI reaction) 1H-imidazo[4,5-C]quinoline of formula XXIX are oxidized using the method used in stage (2) process (reaction scheme II), and the result is 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXX.

At stage (5) process (scheme VI reaction) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXX using the method used in stage (3) process (reaction scheme II), is subjected to the aminating and the result of 1H-imida what about[4,5-C]quinoline-4-amine of formula I.

Proposed in the invention compounds can be obtained according to scheme VII reaction, in which the values of R, R2, X and n are defined above, and the substituent R12represents an aryl group, which may be either unsubstituted, or can contain the substituents specified above.

At the stage (1) process (scheme VII reaction) 1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XIII is subjected to alkylation under the action of a halide of formula XXXI and get 1H-imidazo[4,5-C]quinoline-1-silt ether of formula XXXII. Compound XIII and the halide of formula XXXI are mixed in a two-phase system consisting of a 50%aqueous solution of sodium hydroxide and a suitable solvent, such as dichloromethane, and conducting the reaction in the presence of a catalyst transfer phases, such as benzyltrimethylammonium. The reaction can be conducted at ambient temperature.

At stage (2) process (scheme VII reaction) 1H-imidazo[4,5-C]quinoline of formula XXXII are oxidized, using the methodology used in stage (2) process (reaction scheme II), and get 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXIII.

At stage (3) process (scheme VII reaction) conduct the reaction between 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXIII and trichlorotriazine and get 1H-imidazo[4,5-C]quinoline-4-yl-trichloroacetamide formula XXXIV. Prepost is more isocyanate is added slowly at ambient temperature to a solution of 5N-oxide in an appropriate solvent, such as dichloromethane.

At stage (4) process (scheme VII reaction) 1H-imidazo[4,5-C]quinoline-4-yl-trichloroacetamide formula XXXIV is subjected to hydrolysis and the result is 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXV, which is derived by the coupling of the product of formula II. The hydrolysis can be performed using conventional methods, preferably by treating a solution of the compounds of formula XXXIV in methanol with sodium methylate.

At stage (5) process (scheme VII reaction) conduct the reaction between 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXV and a halide of formula Hal-R12in the presence of transition metal compounds used as the catalyst. The result of 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVI, which is derived by the coupling of the product of formula II. Preferably the interaction of the compounds of formula XXXV with a halide is carried out in the presence of copper iodide (I), dichlorobis(triphenylphosphine) palladium (II) and excess triethylamine in an appropriate solvent, such as N,N-dimethylformamide or acetonitrile. The reaction is preferably carried out at elevated temperature (60-80°). Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds may be obtained in compliance and with the scheme VIII reactions in which R, R2, R12, X and n are defined above. VOS-tert-butoxycarbonyl.

At the stage (1) process (scheme VIII reactions) amino group, 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXV protect two mpem-butoxy carbonyl groups. The reaction between the compound XXXV and di-tert-BUTYLCARBAMATE carried out in an appropriate solvent, such as N,N-dimethylformamide, in the presence of 4-(dimethylamino)pyridine and triethylamine. The reaction is carried out at elevated temperature (80-85°).

At stage (2) process (scheme VIII reactions) protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVII is treated with a halide of formula Hal-R12in the presence of transition metal compounds used as the catalyst, and receive protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVIII. Preferably the compound of formula XXXVII is treated with a halide in the presence of copper iodide (I), dichlorobis(triphenylphosphine) palladium (II) and excess triethylamine in an appropriate solvent, such as N,N-dimethylformamide or acetonitrile. The reaction is preferably carried out at ambient temperature or elevated temperatures (40-80°).

At stage (3) process (scheme VIII reaction of the protective group is removed by hydrolysis in acidic conditions and the result of 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVI, which is produced by the water connection product II. Preferably the compound XXXVIII process triperoxonane acid in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature or cold temperature (0°). Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

At stage (4) process (scheme VIII reactions) alginovu (triple) bond protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVIII restore and the result is a protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXIX. Preferably, the recovery is carried out using a conventional heterogeneous hydrogenation catalyst, such as deposited on activated carbon, palladium or deposited on activated carbon, platinum. The reaction typically can be performed in a Parr apparatus in a suitable solvent, such as methanol.

At stage (5) process (scheme VIII reaction of the protective group of the compounds of formula XXXIX are removed using the method used in stage (3). The result of this reaction get 1H-imidazo[4,5-C]quinoline-4-amine of formula XL, which is derived by the coupling of the product of formula I. the Product or a pharmaceutical salt quality can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can the be obtained according to scheme IX reaction, in which R, R2, R12, X and n are defined above. CBZ-benzyloxycarbonyl.

At the stage (1) process (scheme IX reaction) amino group, 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXV protect benzyloxycarbonylamino groups. The reaction between the compound of formula XXXV and dibenzyldithiocarbamate carried out in an appropriate solvent, such as N,N-dimethylformamide. The reaction is carried out at room or slightly elevated temperature (40°).

At stage (2) process (scheme IX reaction) protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XLI is treated with a halide of formula Hal-R12in the presence of transition metal compounds used as the catalyst, and receive protected 1H-imidazo[4,5-C]quinoline-4-amine of formula XLII. Preferably the compound of formula XLI is treated with a halide in the presence of copper iodide (I), dichlorobis(triphenylphosphine) palladium (II) and excess triethylamine in an appropriate solvent, such as N,N-dimethylformamide or acetonitrile. The reaction is preferably carried out at ambient temperature or elevated temperatures (40-80°).

At stage (3) process (scheme IX reaction of the protective group is removed by hydrolysis and the result of 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVI, which is derived by the coupling of the product of formula II. Preferably the connection of four who uly XLII treated with sodium methylate in a suitable solvent, such as methanol. The reaction can be conducted at ambient temperature. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

At stage (4) process (scheme IX reaction of the protective group of the compounds of formula XLII is removed in the recovery under the action of hydrogen and carry out the restoration of alkyne (triple) bond. The result of 1H-imidazo[4,5-C]quinoline-4-amine of formula XL, which is derived by the coupling of the product of formula I. Preferably the reduction is carried out, using as catalyst hydroxide palladium deposited on activated carbon. The reaction typically can be performed in a Parr apparatus in a suitable solvent, such as methanol. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained in accordance with the scheme X reaction, in which the values of R, R1, R2, X and n are defined above.

At the stage (1) process (scheme X reaction) of 2,4-dichloro-3-nitroquinoline formula XLIII is treated with the amine of formula R1-O-X-NH2and get 2-chloro-3-nitroquinoline-4-amine of formula XLIV. The reaction can be conducted by adding the amine to a solution of compound XLIII in the corresponding races is varicela, such as chloroform or dichloromethane. In some cases the reaction can be conducted under heating. Many quinoline of formula XLIII are either known products or they can be obtained using known synthetic methods (see, for example, with Andre al., U.S. patent No. 4988815 and cited in the literature it).

At stage (2) process (scheme X reaction) of 2-chloro-3-nitroquinoline-4-amine of formula XLIV restore, using for this purpose the method used in stage (2) process (Scheme VI reaction). The result is 2-chlorhydrin-3,4-diamine of formula XLV.

At stage (3) process (scheme X reaction) 2-chlorhydrin-3,4-diamine of formula XLV is subjected to cyclization using the method used in stage (3) process (Scheme VI reaction), and the result is 4-chloro-1H-imidazo[4,5-finalin formula XLVI.

At stage (4) process (scheme X the reaction of 4-chloro-1H-imidazo[4,5-C]quinoline of formula XLVI miniroot to 1H-imidazo[4,5-C]quinoline-4-amine of formula I. the Reaction is carried out under heating (for example, when 125-175° (C) the compounds of formula XLVI in a sealed reactor in the presence of ammonia solution in alkanol. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained according to scheme XI reactions in which the value is s R, R1, R2, X and n are defined above.

In accordance with the scheme XI reactions 1H-imidazo[4,5-C]quinoline-4-amine of formula XLVII under the action of a halide of formula XLVIII to alkylate 1H-imidazo[4,5-C]quinoline-4-amine of formula I. the Compound of formula XLVII is treated with sodium hydride, dispersed in an appropriate solvent, such as N,N-dimethylformamide, and then to the reaction mixture add the halide. The reaction is carried out at elevated temperature (˜100°). The alkylation proceeds as on the nitrogen atom N1 and N3; however, the target product, which is the 1-isomer, can be easily separated from the 3-isomer using conventional methods, for example using chromatographic columns, or by recrystallization.

Many 1H-imidazo[4,5-C]quinoline-4-amines of formula XLVII are either known products or they can be obtained using known synthetic methods, see, for example, Gerster, U.S. Patent No. 5756747 quoted in it literature.

Proposed in the invention compounds can be obtained according to scheme XII reactions, in which the values of R, R1, R2, X and n are defined above.

At the stage (1) process (scheme XII reactions) 4-nitrotetrazolato[1,5-a]quinoline-5-ol of formula XLIX glorious to 5-chloro-4-nitrotetrazolato[1,5-a]quinoline of formula L. For this R the shares can be used gloriouse agents. Mostly the reaction is carried out using phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide. 4-Nitrotetrazolato[1,5-a]quinoline-5-Ola formula XLIX are known compounds or can be obtained by known synthetic methods (see, for example, Gerster, U.S. Patent No. 5741908 and cited in the literature it).

At stage (2) process (scheme XII reactions) conduct the reaction between 5-chloro-4-nitrotetrazolato[1,5-a]quinoline of formula L and an amine of formula R1-O-X-NH2. The result is a 4-nitrotetrazolato[1,5-a]quinoline-5-amine of formula LI. The reaction can be carried out in the presence of triethylamine, adding the amine to a solution of compound LI in an appropriate solvent, such as dichloromethane.

At stage (3) process (scheme XII reactions) 4-nitrotetrazolato[1,5-a]quinoline-5-amine of formula LI restore the method used in stage (2) process (scheme VI reaction), and the result is tetrazolo[1,5-a]quinoline-4,5-diamine of formula LII.

At stage (4) process (scheme XII reaction), using the method applied in stage (3) process (scheme VI reaction), carry out the cyclization tetrazolo[1,5-a]quinoline-4,5-diamine of formula LII to 6N-imidazo[4,5-C]tetrazolo[1,5-a]quinoline of formula LIII.

At stage (5) process (scheme XII reactions) 6N-imidazo[4,5-C]tetrazolo[1,5-a]quinoline of formula LIII reduced to 1H-imidazo[4,5-C]Hino is in-4-amine of formula I. Stage (5) consists of (i) the interaction of the compounds of formula LIII with triphenylphosphine and (ii) subsequent hydrolysis of the resulting product. For holding part (i) heat the mixture of the compounds of formula LIII with triphenylphosphine in an appropriate solvent, such as 1,2-dichlorobenzene. Part (ii) is the hydrolysis product formed in part (i). The hydrolysis may be conducted using conventional methods, such as heating of the product in the presence of water or a lower alcohol, and in some cases in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide of an alkali metal. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained according to scheme XIII reactions, in which the values of R, R2, R12, X and n are defined above.

At the stage (1) process (scheme XIII reactions) 1H-imidazo[4,5-C]quinoline-1-silt ether of the formula XXXII, using the method applied in stage (5) process (scheme VII reaction), is treated with a halide of formula Hal-R12and get 1H-imidazo[4,5-C-]quinoline-1-silt ether of formula LIV.

At stage (2) process (scheme XIII reactions) have oxidation 1H-imidazo[4,5-C]quinoline-1-silt ether of formula LIV according to the method, applied to stage 2 of the process (reaction scheme II), and get 1H-imidazo[4,5-C]quinoline-5N-oxide of formula LV.

Stage (3) process (scheme XIII reaction) is the aminating the product of formula LV according to the method described in stage (3) process (reaction scheme II), and results in 1H-imidazo[4,5-C]quinoline-4-amine of formula XXXVI, which is derived by the connection of the product II. Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained according to scheme XIV reactions, in which the values of R, R2, R12, X and n are defined above.

At the stage (1) process (scheme XIV reactions) restore triple carbon-carbon bond 1H-imidazo[4,5-C]quinoline-1-silt ether of formula LIV, using the method applied in stage (4) process (scheme VIII reaction), and the result is 1H-imidazo[4,5-C]quinoline-1-silt ether of formula LVI.

At stage (2) process (scheme XIV reactions) have oxidation 1H-imidazo[4,5-C]quinoline-1-silt ether of formula LVI according to the method applied in stage (2) process (reaction scheme II), and get 1H-imidazo[4,5-C]quinoline-5N-oxide of formula LVII.

Stage (3) process (scheme XIV reaction) is the aminating 1H-imidazo[4,5-C]quinoline-5N-oxide of formula LVII according to the method used in stage (3) process (reaction scheme II), which results in 1H-imidazo[4,5-C]quinoline-4-amine of formula XL, which is derived by the coupling of the product of formula I. the Product or a pharmaceutical salt quality can be isolated from the reaction mixture using conventional methods.

Proposed in the invention compounds can be obtained in accordance with the scheme XV reactions, in which the values of R, R2, R12, X and n are defined above.

At the stage (1) process (scheme XV reactions) 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XXIV alkylate in the presence of a halide of formula Hal-(CH2)1-10-CH≡SN in accordance with the method used to carry out the process according to scheme V the reaction. The result is 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-amine of formula LVIII, which is derived by the coupling of the product of formula IV.

At stage (2) process (scheme XV reactions) 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]-quinoline-4-amine of formula LVIII alkylate in the presence of a halide of formula Hal-R12in accordance with the method used in stage (5) process (scheme VII reaction). The result is 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-amine of formula LVIX, representing a derivative of the compound of the product of formula IV.

Product or pharmaceutical grade salt can be isolated from the reaction mixture using conventional methods.

PR is alagaesia in the invention compounds can be obtained in accordance with the scheme XVI reactions in which R, R1, R2, X and n are defined above.

At the stage (1) process (scheme XVI reactions) conduct the chlorination of 2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinoline formula LX and receive 2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline formula LXI. For carrying out the reaction using conventional gloriouse agents. Preferably the reaction is performed by adding to the connection LX phosphorus oxychloride and heating the resulting mixture up to 55-65°C. the compounds of formula LX are known products or can be obtained by known synthetic methods (see, for example, Nicolaides with al., U.S. patent 5352784 and cited in the literature it).

At stage (2) process (scheme XVI reactions) conduct the reaction between 2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline formula LXI and Amin R1-O-X-NH2, as a result of 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of formula LXH. The reaction is carried out by adding the amine to a solution of compound LXI in an appropriate solvent, such as N,N-dimethylformamide, and heating the reaction mixture up to 55-65°C.

At stage (3) process (scheme XVI reaction of 2-chloro-3-nitro-6,7,8,9-tetrahydroxy-nolin-4-amine of formula LXII is treated with phenol, using the methodology used in stage (4) process (scheme IV reaction), and the result is 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of formula LXIII.

At stage (4) is the process (scheme XVI reactions), using the methodology applied in stage (2) process (scheme VI reaction), carry out the restoration of 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of formula LXIII 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of formula LXIV.

According to the method used in stage (3) process (scheme VI reaction), stage (5) process (scheme XVI reactions by cyclization of 2-phenoxy-6,7,8,9-tetrahydro-quinoline-3,4-diamine of formula LXIV 4 phenoxy-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]quinoline of formula LXV.

At stage (6) process (scheme XVI reaction), using the methodology used in stage (7) process (scheme IV reaction), 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]quinoline of formula LXV miniroot to 6,7,8,9-tetrahydro-1H-imidazo-[4,5-C]quinoline-4-amine of formula III.

The invention also reported the synthesis of new compounds of interest as intermediate products for preparing compounds of formula (I), (II), (III) and (IV). These intermediate compounds have the structural formula (V)to(IX), details of which are given below.

One class of intermediate compounds has the General formula (V):

where X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl;

- R4aryl; and

- (CH2)1-10-C≡C-R10;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heteroalkyl;

- CO-aryl; and

- CO-heteroaryl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each substituent R3represents independently from each other hydrogen or C1-10alkyl group;

each substituent R10selected from the group consisting of hydrogen atom, alkyl, alkenylphenol and aryl radical;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n can vary from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

Another class of intermediate products is imidazoquinolines-4-phenoxyl the compounds of formula (VI):

where X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl;

- R4-aryl; and

- (CH2)1-10-C≡C-R10;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each substituent R3represents independently from each other hydrogen or C1-10alkyl group;

each substituent R10selected from the group consisting of hydrogen atom, alkyl, alkenylphenol and ailing is radical;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n can vary from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group; or a salt of the pharmaceutical quality on the basis of these groups.

Another class of intermediate products is imidazoquinolines-N-oxide compounds of formula (VII):

where

X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl;

- R4-aryl; and

- (CH2)1-10-C≡C-R10;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each substituent R3represents independently from each other hydrogen or C1-10alkyl group;

each substituent R10selected from the group consisting of hydrogen atom, alkyl, alkenylphenol and aryl radical;

the value of n can vary from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydro is a strong group, the halogen atom and triptorelin group;

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

An additional class of intermediate compounds has the General formula (VIII):

where

X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl;

- R4-aryl; and

- (CH2)1-10-C≡C-R10;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each substituent R3represents independently from each other hydrogen or C1-10alkyl group;

each substituent R10selected from g is PI, consisting of hydrogen atom, alkyl, alkenylphenol and aryl radical;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n can vary from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group; and

Deputy R7represents a tert-boutelou or benzyl group; or a salt of the pharmaceutical quality on the basis of these groups.

And the last class of intermediate products is imidazoquinolines-4-chloro-compounds of formula (IX):

where

X represents-CHR3-, -CHR3-alkyl or-CHR3-alkenylphenol group;

Deputy R1selected from the group including:

- aryl;

alkenyl;

- R4-aryl; and

- (CH2)1-10-C≡C-R10;

R2selected from the group including:

is a hydrogen atom;

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

- alkyl-Y-aryl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group including:

- HE;

is a halogen atom;

- N(R3)2;

- CO-N(R3)2;

- CO-C 1-10alkyl;

- CO-O-C1-10alkyl;

- N3

- aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each substituent R3represents independently from each other hydrogen or C1-10alkyl group;

each group of Y is independently from each other represents-O - or S(O)0-2-;

the value of n can vary from 0 to 4; and

each substituent R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

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

Additionally, the alkyl and Alchemilla part of the groups X may be either unsubstituted, or can contain one or more substituents, and these substituents selected from the group consisting of alkyl, alkenylphenol, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylboronic and geteroseksualnoe groups.

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

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

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

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

Usually only some of the substituents are preferred. For example, the preferred substituent R1is R4-aryl group, and the preferred R10groups are alkyl and aryl group, and the preferred aryl group is phenyl or substituted phenyl group. Preferably, the substituent R was absent (i.e. n=0). Preferred R2groups include a hydrogen atom, alkyl groups containing from 1 to 4 carbon atoms (i.e., methyl, ethyl, sawn, ISO-propyl, n-bucilina, second-bucilina, isobutylene and temporaryily group), methoxymethanol and ethoxymethylene group. For the substituted groups, such as substituted alkyl or substituted aryl group, preferred substituents are halogen atom, nitrile, nitro, carboxyl, metaxylene, methylthiophene, triptoreline and triptoreline group. One or more of these preferred substituents, if present at all, may be contained in the proposed invention the compounds in any combination.

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

Pharmaceutical formulations and biological activity

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

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

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

It is established that proposed in the invention compounds stimulate the production of certain cytokines in the experiments, carried out in accordance with the following testing methods. These results show that the proposed compounds are useful modifiers of the immune response, i.e. they are capable of modulating an immune response in a number of different ways, thereby help in curing various disorders.

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

It is established that we offer some of the invention compounds preferably stimulate the participation of IFN-α change in the number of hematopoietic cells, such as RVS (mononuclear cells peripheral blood)containing pDC2 cells (precursors of dendritic cells type 2)without causing significant concomitant inflammatory cytokines.

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

Offered in izobreteniya impact on the acquired immune response. For example, although believed to offer connections do not have any direct effect on T cells or the formation of T-limfozitah cytokines, these compounds have an indirect influence on the formation of the cytokine IFN-γ from phage-helper type 1 T-lymphocyte (Th1), and the formation of Th2 dysbalance of zikatanov IL-4, IL-5 and IL-13 is slowed down with the introduction described in the invention compounds. These results show that proposed in the present invention compounds assist in the treatment of diseases that require an increase in the number of Th1 and/or reducing the number of Th2 dysbalance. Given the ability of the proposed invention compounds to slow the immune response of the T-phage-helper type 2, it can be expected that these compounds will be useful in the treatment of allergic diseases such as atopic dermatitis, asthma, Allergy, allergic rhinitis, and as an auxiliary vaccine to enhance the immune system, and possibly for the treatment of chronic fungal infections and chlamydia.

Modifying effect of compounds on the immune response makes them useful in the treatment of many different diseases. Due to its ability to stimulate the formation of cytokines, such as IFN-α and/or TNF-αas proposed in the present invention compounds are particularly useful in the treatment of viral the diseases and tumors. This immunomodulating activity suggests that proposed in the invention compounds may be useful in the treatment of such diseases (but not only), as viral diseases such as genital warts, the common warts, plantar warts, hepatitis b, hepatitis C, herpes simplex type I and type II, molluscum contagiosum, smallpox, especially smallpox, HIV, cytomegalovirus, virus varicellazoster, cervical intraepithelial neoplasia, human papilloma virus and associated tumors; influenza and parainfluenza, fungal diseases such as candidiasis, aspergillosis, cryptococcal meningitis, diseases, associated with the appearance of tumors, such as basal cell carcinoma, leukemia "hairy" cells, Kaposi's sarcoma, cancer of renal epithelial cells, cancer cells simple squamous epithelium, leukemia of myelopathy, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous lymphoma, and other cancers; parasitic diseases, for example, pneumocystosis, cryptosporidiosis, histoplasmosis, toxoplasmosis, Trypanosoma infection, leishmaniasis; bacterial infections, such as tuberculosis and mycobacterium avium. Using the proposed in the invention compounds can, in addition, to treat senile keratosis, eczema, eosinophilia, essential thrombocythaemia, leprosy, is rojestvensky sclerosis, the Ommen's syndrome, discoid lupus, Bowen's disease and bowenoid papules, alopecia, inhibition of keloid formation seams after surgical operations and other types of surgical scars. In addition, these compounds can stimulate the healing of wounds, including chronic wounds. They can be also useful for the treatment of opportunistic infections and tumors that appear after the suppression of the immune system, for example, in cancer and HIV patients, as well as after organ transplants.

Effective number of established connections, which is intended to stimulate the biosynthesis of cytokines, is a quantity that is sufficient to induce one or more types of cells, such as monocytes, macrophages, dendritic cells and b-cells, to the formation of one or more cytokines, such as IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, in excess of the background level of such cytokines. The precise effective amount of the compound will vary widely depending on various factors, but it is expected that the effective dose of this compound will be in the range from about 100 ng/kg to about 50 mg/kg, preferably between about 10 μg/kg to about 5 mg/kg

Invented the e also provides a method of treating viral infections and cancer in animals by introducing into the animal an effective amount proposed in the invention compounds or compositions based on it. An effective amount of the compounds for the treatment or suppression of viral infection is the quantity that will result in a decrease one or more symptoms of a viral infection, such as viral lesions, viral load, rate of formation of viruses and increase their mortality compared with the situation observed for control animals not receiving these connections. The exact number of connections will vary widely depending on various factors, but it is expected that the dose of this compound should be in the range from about 100 ng/kg to about 50 mg/kg, preferably between about 10 μg/kg to about 5 mg/kg Effective amount of the compounds for the treatment of cancer is its number, which will result in a decrease in tumor size or number of tumors. And in this case the exact number of connections will vary widely depending on various factors, but it is expected that the dose of this compound should be in the range from about 100 ng/kg to 50 mg/kg, preferably between about 10 μg/kg to about 5 mg/kg

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

Examples

In the examples below, some compounds were purified using prepreparation high-performance liquid chromatography. To this end used two ways, which are discussed below. In both cases used the device A-100 Gilson, equipped with interface 900 series Intelligent Interface. Fractions, obtained on prepreparation chromatograph, were analyzed by mass spectrometric method LC-APCI/MS. The appropriate fractions were combined together and subjected to lyophilization to obtain triperoxonane salt for a compound.

Method And

Column: column Microsorb C18, 21,4×250 mm, particle size 8 μm, the pore size of 60 angstroms. The flow rate of 10 ml/min Gradient elution solvent: the component's contents In eluent was changed from 2 to 95% over 25 min and the eluent with 95%content component was used In within 5 minutes. Component a is 0.1%solution triperoxonane acid in water; the component In the 0.1%solution triperoxonane acid in acetonitrile. Pick a faction that has a maximum absorption at 254 nm.

Method In

Column: Phenomenex Capcell PakC18, 35×20 mm, particle size 5 µm. The flow rate of 20 ml/min Gradient elution solvent: the component's contents In eluent was changed from 5 to 95% within 10 min and eluent with 95%content component was used In within 2 minutes. Component a is 0.1%solution of referencesee acid in water; component In the 0.1%solution triperoxonane acid in acetonitrile. Pick a faction that has a maximum absorption at 254 nm.

Example 1

1[2-(2-Propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine

Part a

28.5 g (of 0.133 mole) of 2-(1H-imidazo[4,5-C]quinoline-1-yl)-1-ethanol added in several portions over 1 hour to a mixture of 240 ml of 50%aqueous sodium hydroxide solution, 240 ml of dichloromethane, to 39.6 g (0,266 mole) 80%propylbromide and 2.46 g (0,013 mol) of benzyltrimethylammonium. The resulting mixture was stirred at ambient temperature for 16 hours. Aqueous and organic layers separated, and the aqueous layer was extracted with additional dichloromethane. The organic layers are combined, washed with water, dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue is added diethyl ether and the mixture is stirred. Solid orange product is filtered and recrystallized from ethyl acetate. The result of 19.8 g of yellow crystalline 2-(1H-imidazo[4,5-C]quinoline-1-yl)ethyl(2-propionovogo) ether. The melting point of this substance 124-126°C.

Analysis. Calculated for C15H13N3ABOUT:%71,70; %N, TO 5.21; %N, 16,72. Found: %71,85; %N, 5,25; %N, 16,90.

1H NMR(300 MHz, DMSO) δ of 9.21 (singlet, 1H); 8,44 (multiplet, 1H); at 8.36 (singlet, 1H); ,18 (multiplet, 1H); 7,71 (multiplet, 2H); 4,93 (triplet, J=5,1 Hz, 2H); 4,14 (doublet, J=2.4 Hz, 2H); 3,98 (triplet, J=5,1 Hz, 2H); 3,55 (triplet, J=2.2 Hz, 1H);

HRMS (mass spectrum high resolution) (ESI) Calculated for C15H13N3O (MH+) 252,1137 found 252,1141.

Part b

19.7 g (78,4 mmole) of 2-(1H-imidazo[4,5-C]quinoline-1-yl)ethyl(2-propionovogo) ether is mixed with chloroform and cooled to 0°C. To the mixture of 15.7 g of 3-chloroperoxybenzoic acid (57-86%) and stirred for 0.5 hour. The mixture is heated to ambient temperature, the entire product goes into solution. Data thin-layer chromatography shows that after this mixture still present a number of the original product. Therefore, to the mixture an additional amount of 3-chloroperoxybenzoic acid (two portions 4 g each). After 0.5 hour after addition of the second portion of the acid, the analysis method of thin-layer chromatography not detected in the mixture of the starting material. The reaction mixture is extracted with 10%sodium hydroxide solution. The aqueous fraction extracted several times with dichloromethane. The organic layers are combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 18.5 g of 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide as a yellow oil.

HRMS(ESI) Calculated for C15H14N3 2(MH+) 268,1086 found 268,1098.

The part With

15.5 g (82.2 mmole) trichloroacetimidate in nitrogen atmosphere are added dropwise to a mixture of 18.3 g (68.5 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide and 300 ml of dichloromethane. There is intense emission of carbon dioxide. After 0.5 hours all the material goes into solution. This solution is stirred for approximately 1 hour and analyzed by the method of thin layer chromatography (TLC). The analysis indicates the presence of a mixture of small quantities of source material. Add 4.5 g trichlorotriazine. After 1 hour, the reaction according to TLC fails completely. Volatile products are removed under reduced pressure and obtain N-[1[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-yl}-2,2,2-trichloroacetamide in the form of a pale yellow solid.

Part D

To a mixture of solid product formed in part C, and 200 ml of methanol, add 150 ml of dichloromethane. The entire product goes into solution. To the solution was added 50 g of sodium methylate (25%solution in methanol) and stirred at a temperature of the environment during the night. The formed precipitate is filtered off. The filtrate is concentrated to a total volume of about 100 ml and filtered again the precipitation. The solid precipitate unite together and dried in a vacuum oven at 60°during the course the e 16 hours. The result of 16.4 g of a whitish solid 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 225-227°C.

Analysis. Calculated for C15H14N4O (H2O)1/4:%C 66,53;%N, 5,40;%N, 20,69. Found: %66,33; %N, 5,18; %N, 21,12.

1H NMR(300 MHz, DMSO) δ 8,13 (singlet, 1H); 8,08 (broad doublet, J=7.8 Hz, 1H); a 7.62 (broad doublet, J=8,3 Hz, 1H); 7,44 (broad triplet, J=7,6 Hz, 2H); from 7.24 (broad triplet, J=7.5 Hz, 2H); 6,54 (singlet, 2H); 4,81 (triplet, J=5.4 Hz, 2H); 4,14 (doublet, J=2.4 Hz, 2H); 3,93 (triplet, J=5,1 Hz, 2H); 3,38 (triplet, J=2.4 Hz, 1H)

HRMS (ESI) Calculated for C15H14N4O (MH+) 267,1246 found 267,1253.

Example 2

2-{3-[2-(4-Amino-1H-imidazo[4,5-quinoline-1-yl)ethoxy]-1-PROPYNYL}benzonitrile

Part a

To 16 g (60,1 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine add to 32.7 g (150 mmol) of di-tert-BUTYLCARBAMATE, 21 ml (150 moles) of triethylamine, and 150 ml of N,N-dimethylformamide and 0.1 g of 4-(dimethylamino)pyridine and the mixture is heated to 80-85°C. After 1 hour, the mixture becomes homogeneous according to TLC contains a very small amount of starting material. The solution is heated for 1 hour, then diluted with water and ethyl acetate. Aqueous and organic layers separated, and the aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed in the Oh and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a pale yellow-orange solid product. After processing this substance diethyl ether get to 22.6 g of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine in the form of a whitish solid, melting point which is 139-142°C.

Analysis. Calculated for C15H30N4O5: %64,36; %N, 6,48; %N, 12,01. Found: %64,40; %N, To 6.43; %N,11,06.

1H NMR(300 MHz, DMSO) δ 8,44 (multiplet, 1H); 8,35 (singlet, 1H); 8,08 (multiplet, 1H); 7,73 (multiplet, 2H); 4,94 (triplet, J=4,9 Hz, 2H); 4,12 (doublet, J=2.4 Hz, 2H); 3,98 (triplet, J=5,1 Hz, 2H); 3,31 (triplet, J=2.4 Hz, 1H); 1,34 (singlet, N)

HRMS(ESI) Calculated for C25H31N4O5(MH+) 467,2294 found 467,2307.

Part b

In nitrogen atmosphere of 0.54 g (2,35 mmole) of 2-iodobenzonitrile, 0.09 g (of 0.13 mmole) dichlorobis(triphenylphosphine)palladium (II) and 0.05 g (of 0.26 mmole) of copper iodide (I) are added to a mixture of 1.0 g (2,14 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine and 25 ml of anhydrous N,N-dimethylformamide. The mixture was incubated for 2 hours and then slowly poured into the water. The precipitate is collected and dried at 35°C for 16 hours. The result is 1.18 g of solid 2-(3-{2-[-(4-(bis-tertbutoxycarbonyl)amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]--PROPYNYL}benzonitrile.

1H NMR(300 MHz, DMSO) δ of 8.47 (doublet, J=6,8 Hz, 1H); 8,39 (singlet, 1H); 8,06 (doublet, J=7.8 Hz, 1H); 7,87 (doublet, J=7,3 Hz, 1H); 7,40-7,80 (multiplet, 4H); 7,34 (doublet, J=7,3 Hz, 1H); 5,00 (broad singlet, 2H); 4,47 (broad singlet, 2H); 4,13 (singlet, 2H); 1,31 (singlet, N)

HRMS(ESI) Calculated for C32H34N5O5(MH+) 568,2560 found 568,2565.

The part With

To a solution of the material obtained in part b, in 20 ml of dichloromethane are added 20 ml triperoxonane acid. After 4 hours the reaction mixture was diluted with dichloromethane containing a small amount of methanol, and 20%sodium hydroxide solution. Aqueous and organic layers separated, and the aqueous layer was extracted with dichloromethane. The organic layers are combined, dried over magnesium sulfate and concentrated under reduced pressure to obtain a yellow powder. This material is purified by way of flash chromatography, using as eluent 9/1 mixture of dichloromethane/methanol, and get to 0.48 g of white powdery 2-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]-1-PROPYNYL}benzonitrile. The melting point of this substance 180-183°C.

Analysis. Calculated for C22H17N5O(H2O)2/5: %70,54; %N, 4,79; %N, 18,70. Found: %70,61; %N, 4,75; %N, 18,70.

1H NMR(300 MHz, DMSO) δ 8,19 (singlet, 1H); 8,12 (doublet, J=8,3 Hz, 1H); 7,88 (doublet, J=7.8 Hz, 1H); 7,55 to 7.75 (multiplet, 3H); 7,40-7,50 (multiplet, 2H); 7.24 to (the wide, triplet, J=7.5 Hz, 1H); 6,68 (broad singlet, 2H); 4,81 (triplet, J=5.4 Hz, 2H); 4,14 (doublet, J=2.4 Hz, 2H); 4,87 (triplet, J=5,1 Hz, 2H); 4,50(singlet, 2H); 4.09 to (triplet, J=5,1 Hz, 1H).

Example 3

1-{2-[(3-Phenyl-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine

A mixture of 10 g (from 37.6 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine, 150 ml of anhydrous N,N-dimethylformamide and 6.23 g (45,1 mmole) of potassium carbonate are heated in a nitrogen atmosphere to 70°C. Add 4,43 ml (39,5 mmole) of odensala, of 0.53 g (0.75 mmole) dichlorobis(triphenylphosphine)palladium (II) and 0.29 grams (1.50 mmole) of copper iodide (I) and the mixture is stirred for 0.5 hours. The temperature was raised to 85°C. Over 1.5 hours to carry out the analysis method high-performance liquid chromatography (reverse phase, acetonitrile/water with 0.1% triperoxonane acid), which shows that the reaction is fully completed. The mixture is cooled to ambient temperature and filtered. The precipitate twice cleanse by way of flash chromatography (95/5 dichloromethane/methanol) and obtain 2.7 g of a white solid of 1-{2-[(3-phenyl-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]-quinoline-4-amine. The melting point of this product 196-197°C.

Analysis. Calculated for C21H18N4O: %73,67; %N, 5,30; %N, 16,36. Found: %73,29; %N, 5,23; %N, 16,35.

1H NMR(300 MHz, DMSO) δ 8.17 (singlet, 1H); 8,12 (doublet, J=7,4 Hz, 2H); 7,63 (double doublet, J=8,3, 0.9 Hz, 1 is); 7,44 (triplet, J=7.5 Hz, 1H); 7,15-7,40 (multiplet, 6N); 6,60 (singlet, 2H); 4,86 (triplet, J=5,1 Hz, 2H); 4,39 (singlet, 2H); 4,03 (triplet, J=5,1 Hz, 2H)

HRMS(EI) Calculated for C21H18N40O (MN+) 342,1481 found 342,1490.

Example 4

Hydrochloric acid 1-{2-[(3-phenyl-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine

1.0 g (2,92 mmole) of 1-{2-[(3-phenyl-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]-quinoline-4-amine dissolved in a mixture of 15 ml methanol and 5 ml of dichloromethane. To the solution add 10 ml of 1 M solution of hydrogen chloride in diethyl ether, and the mixture is stirred for 16 hours. In the process of mixing observed precipitation. The mixture is concentrated under reduced pressure to obtain a solid product. This material is recrystallized from acetonitrile containing a small amount of methanol, and the result is 0.52 g whitish crystalline hydrochloric acid 1-{2-[(3-phenyl-2-PROPYNYL)oxy]ethyl}-1H-imidazo{4,5-C]-quinoline-4-amine. The melting point of this salt 231-236°C.

Analysis. Calculated for C21H19CIN4O(H2O)1/4: %C 65,79; %N, 5,13; %N, 14,61. Found: %C 65,72; %N, 5,0; %N, 14,73.

1H NMR(300 MHz, DMSO) δ 8,49 (singlet, 1H); 8.34 per (doublet, J=8,3 Hz, 1H); 7,81 (broad doublet, J=8,3, 1H); 7,72 (triplet, J=7.8 Hz, 1H); 7,56 (triplet, J=7.8 Hz, 1H); 7,30-7,40 (multiplet, 3H); 7,14 (double doublet, J=8,0, 1.5 Hz, 12); 4,94 (triplet, J=4,8 Hz, 2H); to 4.38 (singlet, 2H); 4,05 (triplet, J=4,9 is C, 2N)

HRMS(EI) Calculated for C21H18N4O (MH+) 342,1481. found 342,1485.

Example 5

1-{2-[3-(4-Methoxyphenyl-2-propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine

Part a

In nitrogen atmosphere to 1.0 g (2,14 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine add 0.8 ml (5,56 mmole) of triethylamine, 0.51 g (2.18 mmole) of 4-iodoanisole and 15 ml of N,N-dimethylformamide. To the mixture is added 0.09 g (of 0.13 mmole) dichlorobis(triphenylphosphine)palladium (II) and 0.05 g (of 0.26 mmole) of copper iodide (I) and stirred for 1 hour at ambient temperature. Analysis of the mixture by the method of high performance liquid chromatography (reverse phase, acetonitrile/water) shows that after this time the reaction is completed. The reaction mixture is distributed between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer is washed with water and then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 0.95 g of N,N-(bis-tert-butoxycarbonyl)-1-(2-{[3-(4-methoxyphenyl)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine in the form of a solid product of orange color.

HRMS(EI) Calculated for C32H36N4O6(MH+) 572,2635 found 572,2635.

Part b

A mixture of 0.75 g (1,31 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-(2-{[3-(4-methox is-phenyl)-2-PROPYNYL]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine, 25 ml of ethyl acetate and 100 mg of catalyst (5% Pd/C with 50% water) hydronaut in a Parr apparatus under hydrogen pressure of 2.8 kg/cm2(40 lb/in2). If this does not leak any reaction. Add 150 mg of platinum oxide and 10 ml of methanol and the mixture hydronaut at 3.15 kg/cm2(45 lb/in2within 1 hour. Immediately noted the consumption of hydrogen. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure and receives a yellow-brown resin, which represents N,N-(bis-tert-butoxycarbonyl)-1-{2-[3-(4-methoxyphenyl)propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine.

HRMS(EI) Calculated for C32H40N4O6(MN+) 576,2948 found 576,2965.

The part With

10 ml triperoxonane acids are added to the mixture of the material obtained in part b, and 10 ml of dichloromethane. The resulting solution was stirred for 4 hours, then concentrated under reduced pressure. The residue is partitioned between 50%aqueous solution of sodium hydroxide and dichloromethane containing a small amount of methanol. The organic fraction is dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a yellow-brown foam product. This product is purified by way of flash chromatography (9/1 dichloromethane/methanol) and get a light yellow glassy ve is esto. This substance is treated with diethyl ether, and then get 0,41 g of a white solid of 1-{2-[3-(4-methoxyphenyl)propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine. The melting temperature of the target product 116-118°C.

Analysis. Calculated for C22H24N4O2: %70,19; %N, TO 6.43; %N, 14,88. Found: %69,79; %N, 6,40; %N, 14,73.

1H NMR(300 MHz, DMSO) δ 8,17 (singlet, 1H); 8,12 (doublet, J=8,3 Hz, 2H); to 7.64 (doublet, J=8,3, 1H); 7,45 (triplet, J=7.8 Hz, 1H); 7.24 to (triplet, J=7,6 Hz, 1H); ); 6,80 (doublet, J=8,8, 2H);); 6,66 (doublet, J=8,8, 2H); 6,60 (singlet, 2H); 4.80 to (triplet, J=5,1 Hz, 2H); 3,81 (triplet, J=4,9 Hz, 2H); 3,66 (singlet, 3H); 3.27 to (triplet, J=6,1 Hz, 2H); 2,32 (triplet, J=7,3 Hz, 2H)and 1.60 (multiplet, 2H).

Example 6

N1,4-Dimethyl-3-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}-1-benzosulfimide

Part a

In nitrogen atmosphere to 1.7 g (6,35 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine type 4,55 g (15.9 mmole) of dibenzyldithiocarbamate, 1.8 ml of triethylamine (13,0 mmole), 4-(dimethylamino)pyridine and 20 ml of N,N-dimethylformamide. The reaction mixture is heated to 90°and at this temperature the mixture rapidly becomes homogeneous. Then, it is heated at 130°C for 4 hours. After that the reaction mixture is cooled and partitioned between dichloromethane and water. The aqueous fraction is extracted with dichloromethane. The organic fractions are combined together, sushi is t over magnesium sulfate and then concentrated to a total volume of about 10 ml. The concentrate is allowed to stand over the weekend and then dilute it with toluene. The precipitate, which was separated by filtration, was identified as the source material. The filtrate is diluted with diethyl ether. After filtering the resulting precipitate obtain 1.1 g benzyl-N-{1-[2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-yl}carbamate as a white solid.

1H NMR(300 MHz, DMSO) δ 9,98 (singlet, 1H); 8.34 per (doublet, J=7.8 Hz, 1H); 8.30 to (singlet, 1H); 7,97 (doublet, J=7,3 Hz, 1H); 7,70 (triplet, J=7,8, 1H); 7,58 (triplet, J =7.8 Hz, 1H); 7,15-7,50 (multiplet, 5H); to 5.21 (singlet, 2H); 4,90 (triplet, J=5,1 Hz, 2H); 4,14 (doublet, J=2.4 Hz, 2H); 3.96 points (triplet, J=4,9 Hz, 2H); 3,38 (triplet, J=2.4 Hz, 2H).

Part b

In nitrogen atmosphere to 0,37 g (of 0.91 mmole) benzyl-N-{1-[2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-yl}carbamate add 0.3 g (0.96 mmole) of 3-iodine-4-methyl-1-benzosulfimide, 0.2 ml (about 1.36 mmole) of triethylamine and 20 ml of anhydrous acetonitrile. To the reaction solution was added 13 mg (0,018 mmole) dichlorobis(triphenylphosphine)palladium (II) and 7 mg (being 0.036 mmole) of copper iodide (I) and the solution is heated to about 45°C. According to high performance liquid chromatography (reverse phase) reaction is completed after 3 hours. The resulting solution was concentrated under reduced pressure, and the residue is purified by way of flash chromatography (98/2 to 95/5 dichloromethane/meth is Nol), resulting in a gain of 0.33 g of benzyl-N-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-yl)carbamate as a pale yellow solid.

1H NMR(300 MHz, DMSO) δ 9,96 (singlet, 1H); at 8.36 (multiplet, 2H); of 7.96 (doublet, J=8,3 Hz, 1H); 7,55-7,70 (multiplet, 4H); of 7.48 (multiplet, 2H); 7,30 was 7.45 (multiplet, 5H); to 5.21 (singlet, 2H); 4.95 points (triplet, J=4,6 Hz, 2H); 4,40 (singlet, 2H); 4,06 (triplet, J=5,1 Hz, 2H); 2,54 (singlet, 3H), 2.40 a (doublet, J=4.9 Hz, 3H) MS(CI) 584,476.

The part With

0.08 g of platinum deposited on charcoal (10%), is added to a mixture of 0.3 g (of 0.51 mmole) benzyl-N-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-PROPYNYL)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-yl)carbamate and 10 ml of methanol. The mixture is subjected to hydrogenation on a Parr apparatus under hydrogen pressure of 40 pounds/inch2(2.8 kg/cm2) for 16 hours. Data analysis the method of liquid chromatography and mass spectrometry (GROMACS analysis) show that the result of this operation is the recovery of the alkyne triple bond, but no evidence of any removal phenoxycarbonyl group. To the reaction mixture is added 0.1 g of palladium deposited on activated carbon (10%), and the hydrogenation continued at the same conditions for 8 hours, the data analysis method of liquid chromatography and mass spectroscopy shows the removal of only a small what about the number peroxycarboxylic group. To the reaction mixture is added 0.1 g of palladium on charcoal and the reaction mixture gidrogenit when the pressure font-inch2(2.8 kg/cm2) for 16 hours. According to GROMACS analysis as a result of this reaction is one main product weight corresponds to the weight of the target product. The reaction mixture was filtered, and the filtrate is washed with methanol and dichloromethane. The solvent is removed under reduced pressure and the result is a whitish solid product, recrystallization from acetonitrile give 0.11 g of N1,4-dimethyl-3-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}-1-benzosulfimide in the form of a pale yellow crystalline solid. The melting point of this product 207-209°C.

Analysis. Calculated for C23H27N5O3S: %60,91; %N, 6,00; %N, 15,44. Found: %In Comparison With 60.87; %N, 5,75; %N, 15,51.

1H NMR(300 MHz, DMSO) δ 8,16 (singlet, 1H); 8,12 (doublet, J=8,3 Hz, 2H); 7,62 (doublet, J=8,3, 1H); 7,53 (doublet, J=1.5 Hz, 1H); 7,44 (broad triplet, J=7,6 Hz, 1H); 7,38 (multiplet, 1H); from 7.24 (broad triplet, J=7,6 Hz, 1H); 7,16 (doublet, J=7,8gts, 1H); 7,02 (double doublet, J=7,8, 2.0 Hz, 1H); 6,58 (singlet, 2H); 4.80 to (triplet, J=5,2 Hz, 2H); 3,82 (triplet, J=5,2 Hz, 2H); 3,31 (triplet, J=5,9 Hz, 2H); 2,47 (singlet, 3H); 2.37 (doublet, J=4.4 Hz, 2H); 1,65 (multiplet, 2H).

HRMS(El) Calculated for C23H27M5O3S (MH+)453,1835, adeno 453,1834.

Example 7

Hydrochloric acid 1-(2-{13-(2-isopropylphenyl)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-finalen-4-amine

A mixture of 0.50 g (of 1.88 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine, 0.65 g (2,63 mmole) of 2-editproperty, 0.68 ml (4,88 mmole) of triethylamine and 10 ml of N,N-dimethylformamide is heated under nitrogen atmosphere to 60°C. To the mixture of 0.08 g dichlorobis(triphenylphosphine)palladium (II) and 0.04 g of copper iodide (I). According to analysis by the method of thin layer chromatography (9/1 dichloromethane/methanol) and the reaction is completed in 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue is purified on a chromatographic column, using as eluent 9/1 mixture of dichloromethane with methanol. Fractions of product are combined together and concentrated under reduced pressure. The residue is purified on a chromatographic column, using as eluent 9/1 mixture of dichloromethane with methanol containing 0.5% concentrated ammonium hydroxide. Fractions of product are combined together and concentrated under reduced pressure to obtain about 0,38 g solids. This substance during the night mixed with 3.9 ml of 1.0 M hydrochloric acid in diethyl ether and then concentrated under reduced pressure. The residue is recrystallized from a mixture of isopropanol/methanol, filtered and after su is Ki obtain 0.24 g of solid hydrochloric acid 1-(2-{[3-(2-isopropylphenyl)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this salt 239-241°C.

Analysis. Calculated for C24H24N4O.HCl.(H2O)1/2: %C 67,06; %N, 6,09; %N, 13,03. Found: %C 67,07; %N, 6,00; %N, To 13.09.

1H NMR(300 MHz, DMSO-d6) δ 8,54 (singlet, 1H); 8,39 (doublet, J=8,1 Hz, 1H); 7,85 (doublet, J=8,2, 1H); 7,76 (triplet, J=7,2 Hz, 1H); to 7.59 (triplet, J=8.0 Hz, 1H); 7,30-7,38 (multiplet, 2H); 7,11-7,19 (multiplet, 2H); 5,00 (triplet, J=4,7 Hz, 2H); 4,47 (singlet, 2H); 4,10 (triplet, J=4,7 Hz, 2H); 3,16 (multiplet, 1H); 1,13 (doublet, J=6,9 Hz, 6N)

IR-spectrum (KBr tablet): 3363, 3111, 2957, 1672, 753 cm-1

HRMS(EI) Calculated for C24H24N4O (M+) 384,1950 found 384,1943.

Example 8

1-(2-{[3-(2,6-Dimetilfenil)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine

Using the primary method used in example 7, conduct the reaction between 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (0.50 g, a 1.88 mmole) and 2,6-dimethylhydantoin (0,61 g, 2,63 mmole). The resulting product was then purified through column chromatography, using as eluent a mixture of 95/5 dichloromethane/methanol, and the result is 0,056 g of solid 1-(2-{[3-(2,6-dimetilfenil)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product 200-201°C.

Analysis. Calculated for C23H22N4O(N2O)2/5: %73,29; %N, 6,07; %N, 14,86. Found: %73,36; %N, 5,88; %N, 14,84.

1H NMR(300 MG IS, DMSO-d6) δ 8.19 (singlet, 1H); 8,13 (doublet, J=8,1 Hz, 1H); 7,62 (doublet, J=7,9,1H); 7,44 (triplet, J=8.0 Hz, 1H); 7.23 percent (triplet, J=7.9 Hz, 1H); 7,09-7,14 (multiplet, 1H); 7,01 -7,03 (multiplet, 2H); 6,76 (singlet, 2H); 4,87 (triplet, J=4,9 Hz, 2H); 4,48 (singlet, 2H); 4,05 (triplet, J=4,9 Hz, 2H); 2,15 singlet, 6N)

IR-spectrum (KBr tablet): 3379, 3065, 1659, 1530, 1483, 1107, 751 cm-1

HRMS(EI) Calculated for C23H22N4O (M+) 370,1794 found 370,1789.

Example 9

1-(2-{[3-(4-Phenoxyphenyl)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-c]quinoline-4-amine

Using the primary method used in example 7, conduct the reaction between 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (0.50 g, a 1.88 mmole) and 4-impenitently ether (0,78 g, 2,63 mmole). The resulting product was then purified through column chromatography, using as eluent a mixture of 95/5 dichloromethane/methanol, and the result is solid. This substance is mixed with an aqueous solution of sodium hydroxide to remove salt, and then purified through column chromatography, using as eluent a mixture of 9/1 ethyl acetate/methanol. Obtained at this stage, the product is subjected to further chromatographic purification, using as eluent a 99/1 mixture of ethyl acetate/methanol, and the result is 24 mg of 1-(2-{[3-(4-phenoxyphenyl)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine, the temperature, p is Alenia which is 146-148° C.

Analysis. Calculated for C27H22N4O2.(H2O)4/5: %72,24; %N, 5,30; %N, 12,48. Found: %71,82; %N, 4,85; %N, 12,35.

1H NMR(300 MHz, DMSO-d6) δ 8,18 (singlet, 1H); 8,12 (doublet, J=7,4 Hz, 1H); 7,62 (doublet, J=7,7, 1H); 7,41-7,47 (multiplet, 3H); 7.18 in-7,27 (multiplet, 4H); 7,06 (double doublet, J=7,6, 1.0 Hz, 1H); 6.90 to (double doublet, J=6,7 Hz, 2H); of 6.71 (singlet, 2H); 4,85 (triplet, J=5,1 Hz, 2H); 4,37 (singlet, 2H); was 4.02 (triplet, J=5.0 Hz, 2H)

IR-spectrum (KBr tablet): 3444, 3070, 2928, 1500, 1230 cm1.

Example 10

1-(2-{3-[2-(Trifluoromethyl)phenyl]-2-PROPYNYL}oxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine

Using the primary method used in example 7, conduct the reaction between 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (0.50 g, a 1.88 mmole) and 2-iodobenzonitrile (0.71 g, 2,63 mmole). The reaction mixture was concentrated under reduced pressure. The obtained glassy product is treated with 10 ml of an aqueous solution of sodium bisulfite and 20 ml of methanol. The solid residue is filtered off. The filtrate is concentrated under reduced pressure to yield a white powder. This material is washed with water and dried in an oven for 4 days at 80°C. Receive about 0.33 g of solids. This substance is partially dissolved in a mixture of 17 ml of dichloromethane and 17 ml of methanol. Then add 3,24 ml of 1.0 M solution of hydrochloric acid in dietro the om ether, resulting mixture becomes homogeneous. After concentration under reduced pressure to obtain a brown crystalline residue, which is connected with a 50/50 mixture of acetonitrile with ethyl acetate containing a small amount of methanol. Add 0.5 ml of 20%sodium hydroxide solution. The mixture is again concentrated to obtain a glassy solid product, which was subjected to purification through column chromatography, using as eluent a mixture of 9/1 ethyl acetate/methanol. The result is 14 mg of white crystalline 1-(2-{3-[2-(trifluoromethyl)phenyl]-2-PROPYNYL}oxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product 154-155°C.

Analysis. Calculated for C22H17F3N4O: %64,39; %N, 4,18; %M, 13,65. Found: %64,39; %N, 4,19; %N, 13,71.

1H NMR(300 MHz, DMSO-d6) δ 8,16 (singlet, 1H); 8,11 (doublet, J=7,4 Hz, 1H); 7,74 (doublet, J=7,3, 1H); 7,56-to 7.64 (multiplet, 3H); 7,38-7,46 (multiplet, 2H); 7,22 (triplet, J=7,6 Hz, 1H); 6,59 (singlet, 2H); 4,87 (triplet, J=5,1 Hz, 2H); 4,45 (singlet, 2H); 4.04 the (triplet, J=5,1 Hz, 2N)

IR-spectrum (KBr tablet): 3375, 3102, 1657, 1583, 1530, 1484, 1320,1103, 765 cm-1.

HRMS(EI) Calculated for C22H17F3N4O (M+) 410,1354 found 410,1350.

Example 11

Triptorelin 1-(2-{3-[4-(1H-1-pyrrolyl)phenyl]-2-propoxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amine

the art And

50 g (174 mmol) of dibenzyldithiocarbamate add in a nitrogen atmosphere to a mixture of 16.4 g (61.6 mmole) 1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine and 200 ml of anhydrous N,N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 16 hours, during mixing, the mixture becomes homogeneous. After that, the reaction mixture is distributed between ethyl acetate and water. Aqueous and organic layers separated, and the aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed with water and then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a semi-solid product. After processing this substance diethyl ether get a 27.4 g of white solid N,N-(bisbenzylisoquinoline)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine.

Part b

In the atmosphere of nitrogen to 0.5 g (0,94 mmole) of N,N-(bisbenzylisoquinoline)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine add 5 ml of anhydrous acetonitrile, 0,34 ml (2,43 mmole) of triethylamine and 0.28 g (of 1.03 mmole) of 1-(4-itfeel)pyrrole and the resulting homogeneous mixture is heated to 80°C. To the reaction solution was added to 0.007 g of copper iodide (I) and (0,013 g dichlorobis(triphenylphosphine)palladium (II). The reaction is completed within 30 minutes. The product was then purified by the method of liquid chromatography, using SMEs/6 hexane/ethyl acetate as eluent, and get a glassy solid. This material is purified by a second column using a mixture of 9/1 hexane/ethyl acetate, and get 0,229 g of N,N-(bisbenzylisoquinoline)1-[2-({3-[4-(1H-pyrrol-1-yl)phenyl]prop-2-inyl}oxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine.

1H NMR(500 MHz, DMSO-d6) δ 8,49 (doublet, J=7.7 Hz, 1H); 8,44 (singlet, 1H); 8,14 (doublet, J=7.9 Hz, 1H); 7,75-to 7.77 (multiplet, 2H); 7,54 (doublet, J=5,1, 2H); 7,40 (singlet, 2H); 7,32 (doublet, J=6,8, 2H); 7.24 to 7,27 (multiplet, 6N); 7,14-7,16 (multiplet, 4H); 6,29 (singlet, 2H); 5,18 (singlet, 4H); 5,00 (triplet, J=5,2 Hz, 2H); 4,42 (singlet, 2H); 4,10 (triplet, J=5,1 Hz, 2H)

MS(CI) for C41H33N5O5m/z 676 (MH+), 632, 524, 408.

The part With

The material obtained in part b, 0.24 g of palladium hydroxide (20%of product deposited on activated carbon) and 5 ml of methanol is loaded into a Parr apparatus and carry out the hydrogenation at a hydrogen pressure of 45 lb/in2(3.2 kg/cm2within 3-4 hours. The reaction mixture was filtered to remove the catalyst, the residue on the filter is washed with additional methanol and the filtrate concentrated under reduced pressure. After purification of the residue using prepreparation high-performance liquid chromatography (method) get 36,6 mg solid trifenatate 1-(2-{3-[4-(1H-1-pyrrolyl)phenyl]-2-propoxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine. Melting point about the ukta 179-181° C.

Analysis. Calculated for C25H25N5OS2HF3O2: %61,71; %N, 4,99; %N, 13,33. Found: %61,49; %N, 4,89; %N, 13,23.

1H NMR(500 MHz, DMSO-d6) δ 8,51 (singlet, 1H); scored 8.38 (doublet, J=8,4 Hz, 1H); 7,84 (doublet, J=8,4 Hz, 1H);7,73 (triplet, J=7,3 Hz, 1H); 7,56 (triplet, J=7.8 Hz, 1H); 7,33 (doublet, J=8,4 Hz, 2H); 7,26 (triplet, J=2.1 Hz, 2H); of 6.96 (doublet, J=8,4 Hz, 2H); 6,24 (triplet, J=8,4 Hz, 1H); 4,91 (triplet, J=5.0 Hz, 2H); 3,85 (triplet, J=5.0 Hz, 2H); 3,3-3,4 (multiplet, 2H) 2,35 (triplet, J=7,6 Hz, 2H); 1.61 of (multiplet, 2H);

IR-spectrum (KBr tablet): 2949, 1705, 1523, 1204, 1123, 721 cm-1.

HRMS(EI) Calculated for C25H25N5O (M+) 411,2059 found 411,2060.

Example 12

Bis(triptorelin) 3-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid

Part a

2,82 g (6,04 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine is added to 2,245 g (6,64 mmole) benzyl-3-iodobenzoate, 2.2 ml (15.7 mmole) of triethylamine and 20 ml of anhydrous acetonitrile, and the resulting homogeneous mixture is heated to 60°C. To the reaction solution was added 0.05 g of copper iodide (I) and 0.08 dichlorobis(triphenylphosphine)palladium (II). The reaction is completed within 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue is purified on a chromatographic column, using as eluent first dichlormethane then the mixture 98/2 dichloromethane/methanol. The result is 1.82 g of benzyl 3-{3-[2-(4-(bis-tert-butoxycarbonyl)amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]prop-1-inyl}benzoate.

1H NMR(300 MHz, DMSO-d6) δ 8,46 (doublet, J=9.6 Hz, 1H); 8,39 (singlet, 1H); 8,05 (doublet, J=9.8 Hz, 1H); 7,94-7,98 (multiplet, 1H); 7,84 (singlet, 1H); 7,50-7,70 (multiplet, 2H); of 7.36-7,49 (multiplet, 7H); are 5.36 (singlet, 2H); 4,98 (triplet, J=4,6 Hz, 2H); 4,37 (singlet, 2H); 4,06-4,13 (multiplet, 2H); 1,30 (singlet, N);

MS(CI) for C39H40N4O7m/z 677 (MH+), 577, 477.

Part b

A solution of material from part a in methanol is combined with a catalyst (1.0 g of palladium (10%)supported on activated carbon) and carry out the hydrogenation at a pressure of 45 lb/in2(3.2 kg/cm2) at ambient temperature for about 2.25 hours. Then add 0.3 g of catalyst and the hydrogenation continued for 2 hours. The reaction mixture was filtered to remove the catalyst, the filter residue is thoroughly washed with methanol. The filtrate is concentrated under reduced pressure to obtain about 1.2 g of N,N-(bis-tert-butoxycarbonyl) 3-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid.

1H NMR(300 MHz, DMSO-d6) δ 8,50 (doublet, J=9.5 Hz, 1H); 8,40 (singlet, 1H); 8.07-a 8,10 (multiplet, 1H); 7,70 to 7.75 (multiplet, 1H); 7,65 (singlet, 1H); 1,29 (singlet, N); 7,29 (triplet, J=7,6 Hz, 1H); 7,10 (doublet, J=7.8 Hz, 1H); 4,94 (triple the t, J=4.5 Hz, 2H); 3,88 (triplet, J=4.5 Hz, 2H); 3,32 (triplet, J=6.0 Hz, 2H); 2,43 (triplet, J=7,0 Hz, 2H); 1,62 (multiplet, 2H);

MS(CI) for C32H38N4O7m/z 591 (MN+), 491, 391.

The part With

The material obtained in part b, in nitrogen atmosphere combined with 10 ml of anhydrous dichloromethane and 10 ml triperoxonane acid. The reaction mixture was stirred for 1.5 hours, then concentrated under reduced pressure to obtain oil, which after drying at ambient temperature in a high vacuum gives a solid product. This product is treated with ether. Resulting white powder is dried overnight in a vacuum oven at 65°and the result is 1.19 g of bis(triptoreline) 3-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}-benzoic acid. The melting point of the product 138-140°C.

Analysis. Calculated for C22H22N4O3.(C2HF3O2)2: %50,49; %N, 3,91; %N, 9,06. Found: %50,37; %N, 3,67; %N, The Remaining 9.08.

1H NMR(300 MHz, DMSO-d6) δ 9,07-9,14 (broad singlet, 2H); 8,51 (singlet, 1H); of 8.37 (doublet, J=7.8 Hz, 1H); 7.82 (doublet, J=8.0 Hz, 1H); 7,74 (multiplet, 2H); to 7.64 (singlet, 1H); 7,56 (triplet, J=7,1 Hz, 1H); 7,30 (triplet, J=7.7 Hz, 1H); 7,15 (doublet, J=7,6 Hz, 1H); 4,91 (triplet, J=4.5 Hz, 2H); 3,86 (triplet, J=4.4 Hz, 2H); 3.42 points (triplet, J=5,9 Hz, 2H); 2,44 (triplet, J=7,4 Hz, 2H); 1,64 (multiplet, 2H);

IR-spectrum (in tablet KBR): 3367, 3104, 2372,1685, 1204, 1146 cm-1.

HRMS(EI) Calculated for C22H22N4O3(M+) 390,1692 found 390,1690.

Example 13

Triptorelin 2-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid

Part a

Using the primary method used in part a of example 12, the reaction between N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (2 g, 4.3 mmole) and benzyl-2-iodobenzoate (1,57 g, 4,71 mmole) get to 1.79 g of a mixture of mono - and di-substituted benzyl-2-{3-[2-(4-amino-1H-imidazo[4,5-finalen-1-yl)ethoxy]prop-1-inyl}benzoate containing as Deputy protective BOC-group.

1H NMR(300 MHz, DMSO-d6) δ 8,45 (doublet, J=7.9 Hz, 1H); 8,39 (singlet, 1H); 8,06-8,09 (multiplet, 1H); a 7.85-7,88 (multiplet, 1H); 7,70-7,73 (multiplet, 2H); 7,47-7,51 (multiplet, 2H); 7,40-7,43 (multiplet, 2H); 7,28-7,37 (multiplet, 3H); 7,19 (multiplet, 1H); 5,23 (singlet, 2H); equal to 4.97 (triplet, J=5.0 Hz, 2H); 4,27 (singlet, 2H); 4,07 (triplet, J=4,9 Hz, 2H); 1,30 (singlet, N);

MS(CI) for C39H40N4O7m/z 677 (MN+), 577, 477.

Part b

Using the primary method used in part b of example 12, the material obtained in part a of this example, hydronaut and get 0,041 g mono - and di-substituted 2-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid, containing as a substituent the safety of the BOC-group.

1H NMR(300 MHz, DMSO-d6) δ 8,50 (doublet, J=7,3 Hz, 1H); 8,39 (singlet, 1H); 8,08 (doublet, J=7.9 Hz, 1H); 7,71 to 7.75 (multiplet, 3H); 7,22-7,28 (multiplet, 2H); 6.90 to (doublet, J=7,4 Hz, 1H); 4,93 (triplet, J=4,6 Hz, 2H); a 3.87 (triplet, J=4.5 Hz, 2H); 3,30 (triplet, J=5.6 Hz, 2H); 2,73 (triplet, J=5.7 Hz, 2H); 1.61 of (multiplet, 2H); 1.28 (in the singlet, N);

MS(CI) for C32H38N4O7m/z 591 (MN+), 491, 391.

The part With

Using the primary method used in part C of example 12, the material obtained in part b of this example, is subjected to hydrolysis and obtain 0.28 g of 2-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid. The melting point of 186-188°C.

Analysis. Calculated for C22H22N4O3C2HF3O2: %57,14; %N, 4,59; %N, 11.11 IS. Found: %56,81; %N, 4,47; %N, 1108.

1H NMR(300 MHz, DMSO-d6) δ 8,90-9,20 (broad singlet, 1H); 8,50 (singlet, 1H); scored 8.38 (doublet, J=10.1 Hz, 1H); 7,84 (doublet, J=8,3 Hz, 1H); 7,71 to 7.75 (multiplet, 2H); 7,56 (triplet, J=7,6 Hz, 1H); 7,21-7,32 (multiplet, 2H); 6,88 (doublet, J=6,9 Hz, 2H); 4,90 (triplet, J=4,8 Hz, 2H); 3,84 (triplet, J=4,6 Hz, 2H); 3,32 (multiplet, 2H); 2,72 (triplet, J=6,9 Hz, 2H); 1,62 (multiplet, 2H);

IR-spectrum (KBr tablet): 3212, 2929, 1709, 1204, 1124, 747 cm-1.

HRMS(EI) Calculated for C22H22N4O3(M+) 390,1692 found 390,1693.

Example 14

Triptorelin 4-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic sour is s

Part a

Using the primary method used in part a of example 12, the reaction between N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-finalen-4-amine (2,82 g, 6,04 mmole) and benzyl-4-iodobenzoate (2.25 g, 6,64 mmole) obtain 2.14 g of a mixture of mono - and di-protected benzyl-4-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]prop-1-inyl}benzoate containing as Deputy protective BOC-group.

1H NMR(300 MHz, DMSO-d6) δ of 8.47 (doublet, J=7,2 Hz, 1H); 8,40 (singlet, 1H); 8,06 (doublet, J=6.5 Hz, 1H); 7,87-7,89 (multiplet, 1H); 7,70-7,73 (multiplet, 2H); of 7.36-7,49 (multiplet, 5H); 7.23 percent-7,27 (multiplet, 2H); 5,35 (singlet, 2H); 5,0 (triplet, J=4.5 Hz, 2H); 4,40 (singlet, 2H); 4.09 to (triplet, J=4.5 Hz, 2H); 1,30 (singlet, N);

MS(CI) for C39H40N4O7m/z 677 (MN+), 577, 477.

Part b

Using the primary method used in part b of example 12, the material obtained in part a of this example, hydronaut and obtain 1.86 g of mono - and di-substituted 4-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid, containing as Deputy protective BOC-group.

1H NMR(300 MHz, DMSO-d6) δ 8,51 (doublet, J=7,1 Hz, 1H); 8,40 (singlet, 1H); 8.07-a 8,10 (multiplet, 1H); 7,72 to 7.75 (multiplet, 3H); 7,01 (doublet, J=8,4 Hz, 1H); 4,94 (triplet, J=4,7 Hz, 2H); 3,88 (triplet, J=4,6 Hz, 2H); 3,30 (multiplet, 2H); 2,38 (triplet, J=7,3 Hz, 2H); 1,62 (Prov.multiplet, 2H); 1,29 (singlet, N);

MS(CI) for C32H38N4O7m/z 591 (MH+), 491, 391.

The part With

Using the primary method used in part C of example 12, the material obtained in part b of this example, is subjected to hydrolysis and obtain 0.96 g of triptoreline 4-{3-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]propyl}benzoic acid. Melting point 235-237°C.

Analysis. Calculated for C22H22N4O3.C2HF3O2: %57,14; %N, 4,59; %N, 11.11 IS. Found: %57,06; %N, 4,47; %N, 11,03.

1H NMR(300 MHz, DMSO-d6) δ 9,00-9,11 (broad singlet, 1H); 8,51 (singlet, 1H); of 8.37 (doublet, J=8,4 Hz, 1H); 7,83 (doublet, J=6.0 Hz, 1H); 7,71-7,76 (multiplet, 3H); 7,55 (triplet, J=9.7 Hz, 1H); 7,01 (doublet, J=8,2 Hz, 2H); 4,91 (triplet, J=5.0 Hz, 2H); 3,84 (triplet, J=4,7 Hz, 2H); 3,32 (triplet, J=5.8 Hz, 2H); 2,38 (triplet, J=7,1 Hz, 2H); 1,62 (multiplet, 2H);

IR-spectrum (KBr tablet): 3266, 3014, 2361, 1667, 1277, 1201, 1142 cm-1.

HRMS(EI) Calculated for C22H22N4O3(M+) 390,1692 found 390,1697.

Example 15

The dihydrochloride of 1-(2-{3-[3-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in part a of example 12, only at a temperature of 80°With, in the reaction between N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (3 g, to 6.43 m is Olya) and 3-iodine-N,N-dimethylaniline (7,07 mmol) get a 3.06 g of a mixture of monoamino and unprotected 1-[2-({3-[3-(dimethylamino)phenyl]prop-2-inyl}oxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine.

Part b

Using the primary method used in part b of example 12, the material obtained in part a of this example, hydronaut and receive approximately 2.9 g of the mixture monoamino tert-butoxycarbonyl group and unprotected 1-(2-{3-[3-(dimethylamino)phenyl]propoxy}ethyl]-1H-imidazo[4,5-C]quinoline-4-amine.

The part With

The material obtained in part b, add 30 ml of 3 M solution of hydrogen chloride in methanol and the mixture was stirred at ambient temperature for 19 hours. The formed precipitate is filtered off. The filtrate is concentrated under reduced pressure, and the residue is dissolved in a small amount of methanol, and then neutralized with a concentrated solution of ammonium hydroxide to achieve a pH˜11. The precipitate purified through column chromatography, using as eluent a mixture of 95/5/1 dichloromethane/methanol/ammonium hydroxide. This material is combined with a system of hydrogen chloride/diethyl ether. The resulting solution was concentrated under reduced pressure. The residue is treated with diethyl ether. The formed solid is filtered off and after drying receive 0,114 g of the dihydrochloride of 1-(2-{3-[3-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product 180-183°C.

Analysis. Calculated for C23H27N5O.(HCl)2,1/sub> (H2O)2,1: %C 54,82; %N, 6,66; %N, 13,89. Found: %C 54,60; %N, 6,50; %N, 13,66.

1H NMR(300 MHz, DMSO-d6) δ 8,71-8,73 (broad singlet, 2H); 8,44 (singlet, 1H); 8,35 (doublet, J=7,4 Hz, 1H); 7,83 (doublet, J=8.0 Hz, 1H); 7,72 (triplet, J=7,6 Hz, 1H); 7,55 (triplet, J=6,8 Hz, 1H); 7,15 (multiplet, 1H); 7,05 (multiplet, 1H); of 6.96 (singlet, 1H); 6,66 (doublet, J=8,1 Hz, 1H); 4,88 (triplet, J=5.3 Hz, 2H); was 4.02 (triplet, J=3,7 Hz, 2H); 3,37 (triplet, J=6,4 Hz, 2H); 2,94 (singlet, 6N); 2.40 a (triplet, J=7,6 Hz, 2H); 1,66 (multiplet, 2H);

IR-spectrum (KBr tablet): 3426, 3138, 2928, 1693, 1113 cm-1.

HRMS(EI) Calculated for C23H27N5O (M+) 389,2216 found 389,2217.

Example 16

Hydrochloric acid 2-(ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

3.50 g (12.9 mmole) 2-[2-(Ethoxymethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol slowly over 20 minutes added to a suspension of 0.67 g (60% in mineral oil, 16,77 mmole) of sodium hydride in anhydrous N,N-dimethylformamide. The reaction mixture is stirred for 1 hour and then add 2,16 ml (14,19 mmole) 1-bromo-3-phenylpropane, after which stirring is continued over night. The reaction mixture was diluted with ethyl acetate, washed with water and then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified on a chromatographic column, using as eluent the ethyl acetate and the result of 2.38 g of 2-(ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline as a yellow oil.

MS(CI) for C24H27N3O2m/z 390 (MH+), 346.

Part b

The material obtained in part a, is combined with 50 ml of chloroform and cooled to 0°C. To the cooled mixture is added 2,22 g of 57-86%3-chloroperoxybenzoic acid. After 1 hour the reaction mixture is heated to ambient temperature and partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic fraction is dried over magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a brown solid product, which represents a 2-(ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide.

The part With

To a mixture of the material obtained in part b, and 60 ml of anhydrous dichloromethane under nitrogen atmosphere add to 0.87 ml (7,33 mmole) trichloroacetimidate. After 1 hour the reaction mixture was concentrated under reduced pressure and get 2,2,2-trichloro-N-{2-(ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-1-yl}ndimethylacetamide.

Part D

To a mixture of the product obtained in part C, and 30 ml of methanol add 4,79 ml of 25%solution of sodium methylate in methanol. The reaction mixture is stirred overnight and then concentrated under reduced pressure to obtain to ichnevogo oil. This oil is purified on a chromatographic column, using as eluent dichloromethane containing 5% methanol, and get a light yellow oil. When processing this oil 1.0 M solution of hydrochloric acid to obtain white solid, which was filtered and dried overnight in a vacuum oven at 80°C. the result of 0.79 g of a white solid hydrochloric acid 2-(ethoxymethyl)-1-[2-(3-phenylpropoxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product 128-134°C.

Analysis. Calculated for C24H28N4O2.1,55 HCl: %62,53; %N, 6,46; %N, 12, And 15. Found: %62,64; %N, 6,47; %N, 11,91.

1H NMR(300 MHz, DMSO-d6) δ to 8.14 (broad doublet, J=8,3 Hz, 1H); 7,63 (double doublet, J=8,3, 1.0 Hz, 1H); 7,45 (multiplet, 1H); 7.24 to (multiplet, 1H); 7,05-7,15 (multiplet, 3H); 6.90 to (multiplet, 2H); 6,62 (singlet, 2H); 4.80 to 4,90 (multiplet, 4H); 3,83 (triplet, J=5.4 Hz, 2H); 3,56 (Quartet, J=7,0 Hz, 2H); 3.27 to (triplet, J=6,1 Hz, 2H); 2.37 (triplet, J=7,6 Hz, 2H); 1,63 (multiplet, 2H); 1,16 (triplet, J=6,8 Hz, 3H)

IR-spectrum (KBr tablet): 3267, 3023, 1681, 1108 cm-1.

HRMS(EI) Calculated for C24H28N4O2(M+) 404,2212 found 404,2215.

Example 17

1-(1-{[(3-Chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

3.0 g (12,43 mmole) of 2-ethyl-2-(1H-imidazo[4,5-C]quinoline-1-yl)ethanol is added to a mixture of 40 ml of dihormati is a, 40 ml of 50%aqueous sodium hydroxide solution, 0.01 g of benzyltrimethylammonium and of 2.81 g (13,67 mmole) 3-chlorobenzylamino. The resulting solution was stirred at ambient temperature overnight. After that, according to analysis by the method of thin layer chromatography (5% methanol in dichloromethane) and the reaction is completed. After the reaction mixture is diluted with 100 ml dichloromethane and 100 ml of water. Separate organic and aqueous layers. The aqueous fraction is extracted with dichloromethane. The combined organic fractions washed with brine, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by way of flash chromatography (silica gel, eluent - ethyl acetate) and get 4,22 g light orange oily 1-(1-{[(3-Chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline.

1H NMR(300 MHz, DMSO-d6) δ which 9.22 (singlet, 1H), 8,63 (singlet, 1H), 8,55 (doublet, J=7.8 Hz, 1H); 8.17 and (double doublet, J=7,8, 1.5 Hz, 1H); 7,69 (multiplet, 2H); 7.23 percent (double doublet, J=4,9, 1.5 Hz, 2H); 7,08 (singlet, 1H), 7,03 (multiplet, 1H), 5.40 to (multiplet, 1H), 4,47 (singlet, 2H); 3,34-4,07 (multiplet, 2H), 2,11 (multiplet, 2H); from 0.88 (triplet, J=7,3 Hz, 3H);

MS(CI) for C21H20CIN3About m/z 366 (MH+), 322.

Part b

To a solution of the material obtained in part a, 60 ml of chloroform are added in several portions 2,84 g 77%chloroperoxybenzoic is islote. According to analysis by the method of thin layer chromatography (10% methanol in dichloromethane) and the reaction is completed in 2 hours. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and then brine, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 1-(1-{[(3-Chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline-5N-oxide.

The part With

To a solution of the material obtained in part b, in 80 ml of dichloromethane are added 20 ml of ammonium hydroxide, and then portions 2,42 g chloride Totila. According to analysis by the method of thin layer chromatography (5% methanol in dichloromethane) and the reaction is completed immediately after the addition of chloride Totila. The reaction mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate. Separate organic and aqueous layers. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a light brown oil. This oil is purified by way of flash chromatography (silica gel, eluent - dichloromethane containing 5% methanol) and get a sticky whitish solid product. Purification of this product by way of flash chromatography (silica gel, eluent - dichloromethane containing 5% methanol) gives a pinkish-white solid p is oduct. This product is again purified by way of flash chromatography (silica gel, eluent - ethyl acetate) and the result is about 1.0 g of a whitish solid 1-(1-[[(3-Chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 60-62°C. the Analysis.

Calculated for C21H21ClN4O% H2O: %65,41; %N, 5,62; %N, 14,54. Found: %65,5; %N, 5,62; %N, 14,61.

1H NMR(300 MHz, DMSO-d6) δ of 8.37 (singlet, 1H), 8,19 (doublet, J=8,3 Hz, 1H); 7,62 (double doublet, J=8,3, 1.5 Hz, 1H); 7,43 (double triplet, J=8,3, 1.5 Hz, 1H); 7.18 in-7,28 (multiplet, 3H); 7,09 (multiplet, 1H); of 6.52 (broad singlet, 2H); 5,24 (multiplet, 1H); 4,48 (singlet, 2H), 4,01 (double doublet, J=10,5, and 6.6 Hz, 2H), 3,92 (double doublet, J=10,3, 4,4 Hz, 2H), 2,10 (Quartet, J=7,3 Hz, 2H), from 0.88 (triplet, J=7,3 Hz, 3H)

MS(CI) for C21H21ClN4O m/z 381 (MH+), 185.

Example 18

Triptorelin 1-{2-[3-(2-AMINOPHENYL)propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine

Part a

0.50 g (1,07 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine, of 0.39 ml (2,79 mmole) of triethylamine and 10 ml of anhydrous acetonitrile are mixed in a nitrogen atmosphere. The resulting solution was heated to 80°and add to it of 0.26 ml (1,18 mmole) 2-iodoaniline, 0,012 g of copper iodide (I) and (0,023 dichlorobis(triphenylphosphine)palladium (II). The mixture was kept at 80°during the course the e night. The acetonitrile is distilled off under reduced pressure, the residue is purified by way of flash chromatography (silica gel, eluent - dichloromethane containing 3% methanol) and the result of 0.47 g of brown solid N,N-(bis-tert-butoxycarbonyl)-1-[2-{[3-(2-AMINOPHENYL)prop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine.

1H NMR(300 MHz, DMSO-d6D2O) δ of 8.47 (doublet, J=3,6 Hz, 1H); of 8.37 (singlet, 1H); 8,10 (doublet, J=9.6 Hz, 1H); 7,75 (multiplet, 2H);? 7.04 baby mortality (triplet, J=7,2 Hz, 1H); 6,80 (multiplet, 1H), 6,65 (doublet, J=8,3 Hz, 1H); 6,45 (triplet, J=7,3 Hz, 1H); 4,98 (triplet, J=4.4 Hz, 2H); 4,36 (singlet, 2H), 4,08 (triplet, J=4,9 Hz, 2H); 1,31 (singlet, N).

Part b

To a solution of N,N-(bis-tert-butoxycarbonyl)-1-[2-{[3-(2-AMINOPHENYL)prop-2-inyl]-oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine in methanol add the catalyst (activated carbon coated with a 5% platinum). The mixture is subjected to hydrogenation in a Parr apparatus under hydrogen pressure of 50 lb/in2(3.5 kg/cm2) during the night. After that the reaction mixture is filtered through a layer of Celite® and the residue on the filter is washed with additional methanol. The filtrate is concentrated under reduced pressure to obtain a whitish solid product. This material is purified by way of flash chromatography on silica gel, using as eluent first dichloromethane, then the mixture is 99/1 dichloromethane/methanol and then a mixture of these W the solvent composition 98/2 and finally a 97/3 mixture of dichloromethane/methanol. The result is about 0.25 g of light yellow oily N,N-(bis-tert-butoxycarbonyl)-1-{2-13-(2-AMINOPHENYL)-propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine.

1H NMR(300 MHz, DMSO-d6) δ 8,23 (double doublet, J=8,4, 0.9 Hz, 1H), 8,16 (double doublet, J=8,4, 0.9 Hz, 1H), 7,97 (singlet, 1H), of 6.96 (double triplet, J=7,5, and 1.6 Hz, 2H), 6.87 in (double doublet, J=7,5, and 1.4 Hz, 1H), 6,62 (double triplet, J=7,3, 1.0 Hz, 1H), 6,57 (double doublet, J=8,3, 1.1 Hz, 1H), from 5.29 (singlet, 1H), 4,71 (triplet, J=5.3 Hz, 2H); 3,91 (triplet, J=5,1 Hz, 2H), 3,38 (triplet, J=6.0 Hz, 2H), 2,39 (triplet, J=7,4 Hz, 2H), 1,76 (multiplet, 2H), 1,41 (broad singlet, N).

MS(CI) for C31H39N5O5m/z 562 (MH+), 462, 362, 229.

The part With

A solution of the material obtained in part b, in 4 ml of dichloromethane was added with stirring to a cooled to 0°With solution 2 ml triperoxonane acid in 2 ml of anhydrous dichloromethane. The reaction mixture was incubated for 2 hours in an ice bath, and then heated to ambient temperature and kept at this temperature during the night. After distillation of the volatile products from the reaction mixture remains rose oil. This oil is dissolved in 3 ml of ethyl acetate and to the solution are added dropwise to about 1 ml of triethylamine, after which the mixture is stirred for 1 hour. The precipitate is filtered off and gain of 0.13 g of a white solid three is taratata 1-{2-[3-(2-AMINOPHENYL)propoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine.

Analysis. Calculated for C21H23N5OS2HF3O2: %58,10; %N, 5,09; %N, 14,73. Found: %57,78; %N, Equal To 4.97; %N, 14,59.

1H NMR(300 MHz, DMSO-d6) δ 8,87 (broad singlet, 1H), 8,49 (singlet, 1H), at 8.36 (doublet, J=7.8 Hz, 1H); 7,83 (doublet, J=8,3 Hz, 1H); 7,72 (triplet, J=7,3 Hz, 1H), 7,56 (triplet, J=7,6 Hz, 1H), for 6.81 (triplet, J=7,6 Hz, 1H), 6,51 (multiplet, 2H); 6,32 (triplet, J=6,8 Hz, 1H), 4,90 (triplet, J=4,6 Hz, 2H), 3,85 (triplet, J=4,9 Hz, 2H), 3.33 and (triplet, J=6,1 Hz, 2H), 2,22 (triplet, J=736 Hz, 2H), 1.55V (multiplet, 2H)

IR-spectrum (KBr tablet): 3414, 3335, 3253, 3019,1738, 1202, 1185, 1131 cm-1.

HRMS(EI) Calculated for C21H23N5O (M+)361,1903 found 361,1903.

Example 19

4-{[2-(4-Amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]methyl}benzonitrile

Part a

1.5 g (7.0 mmole) of 2-(1H-imidazo[4,5-C]quinoline-1-yl)ethanol was added with stirring to a mixture of 1,79 g (9.1 mmole) α-bromo-p-toluenethiol, 20 ml of 50%aqueous sodium hydroxide solution, 20 ml dichloromethane and 0.06 g (0.3 mmole) of benzyltrimethylammonium. The reaction continued for 18 hours and then the reaction mixture is diluted by adding 20 ml of dichloromethane and 20 ml of water. Separate organic and aqueous layers. The aqueous fraction is extracted with additional dichloromethane. The organic fractions are combined together, washed with water, dried over magnesium sulfate and concentrated. The remainder under the will eraut clearing the way flash chromatography (silica gel, eluent is a mixture of 9/1 dichloromethane/methanol) and obtain 1.8 g of 4-{[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]methyl}benzonitrile.

1H NMR(500 MHz, DMSO-d6) δ which 9.22 (singlet, 1H), to 8.41 (singlet, 1H), 8,40 (doublet, J=1.1 Hz, 1H); 8.17 and (double doublet, J=7,6, 1.3 Hz, 1H); 7,66 (double triplet, J=7,6, 1.3 Hz, 1H), 7,56 (triplet, J=7,6 Hz, 1H), for 6.81 (triplet, J=7,6 Hz, 1H), 6,51 (multiplet, 2H); 7,63 (doublet, J=8,3 Hz, 2H), 7,25 (doublet, J=8,2 Hz, 2H), equal to 4.97 (triplet, J=5,1 Hz, 2H), 4.53-in (singlet, 2H), 3,97 (triplet, J=5.5 Hz, 2H);

MS(CI) m/z 329 (M+N).

Part b

1.6 g (5.5 mmole) of 60%3-chloroperoxybenzoic acid is added slowly to a solution of 1.8 g (5.5 mmole) of 4-{[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethoxy-methyl}-benzonitrile in 50 ml of chloroform. The reaction mixture was incubated overnight (about 16 hours), then washed successively with 200 ml saturated sodium bicarbonate solution and two portions of water, 100 ml each), dried over magnesium sulfate, filtered and concentrated to obtain 1.4 g of 1-{[2-[(4-cyanobenzyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide.

The part With

To a solution of 1.4 g (4.1 mmole) of 1-{[2-[(4-cyanobenzyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide in 25 ml of dichloromethane are added dropwise to 0.73 ml (6.1 mmole) trichloroacetimidate. The reaction mixture was kept overnight and then concentrated. The resulting solid red dissolved in 100 ml of methanol, to the solution is added dropwise 4ml 25%solution of sodium methylate in methanol and again incubated the reaction mixture during the night. The resulting solid precipitate is filtered off. As a result of recrystallization of this product from isopropyl alcohol and then flash chromatographic purification (silica gel, 9/1 dichloromethane/methanol) to obtain 1.0 g of a white solid of 4-{[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]methyl}benzonitrile, melting point which is 238,1-239,2°C.

1H NMR(300 MHz, DMSO-d6) δ 8,19 (singlet, 1H), 8,07 (double doublet, J=8,2, 1.0 Hz, 1H); to 7.67 (doublet, J=8,4 Hz, 2H), 7.62mm (double doublet, J=8,4, 1.1 Hz, 1H), 7,43 (double triplet, J=7,6, 1.3 Hz, 1H), 7,30 (doublet, J=8,4 Hz, 2H), 7,21 (double triplet, J=7,6, 1.3 Hz, 1H), 6,56 (singlet, 2H), 4,86 (triplet, J=5,1 Hz, 2H), 4,55 (singlet, 2H), 3,93 (triplet, J=5,1 Hz, 2H);

IR-spectrum (KBr tablet): 3456, 3285, 3117, 3069, 2228, 1637, 1583, 1526, 1481, 1397, 1372, 1353, 1252, 1097, 884, 822, 760 cm-1.

MS (El) m/e 343.1440 (343.1433. Calculated for C20H17N5O);

Analysis. Calculated for C20H17N5O: %69,96; %N, 4,99; %N, 20,39. Found: %70,09; %N, 4,90; %N, 20,16.

Example 20

2-(Ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amine

Part a

A solution of 1.0 g (3.7 mmole) 2-[2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol in 20 ml of N,N-dimethylformamide is added dropwise to a suspension of sodium hydride (0,19 g of 60%suspension in mineral oil, 4.8 mmole) in 10 ml of N,N-dimethylformamide. The mixture is kept for the duration-45 minutes and then added dropwise thereto 1.6 g (5.1 mmole) of {4-[(6-bromohexyl)oxy]butyl}benzene. The reaction mixture was stirred at ambient temperature overnight, and then distributed between ethyl acetate and water. Separate organic and aqueous layers. The aqueous fraction is extracted with additional ethyl acetate. The organic fractions are combined together, washed with water, dried over magnesium sulfate and concentrated. The residue is purified by way of flash chromatography (silica gel, eluent is a mixture 4/1 ethyl acetate/hexane) and get 0,81 g of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)hexyl]oxy}ethyl)-1H-imidazo-[4,5-C]-quinoline as a brown oil.

Part b

of 0.47 g (1.6 mmole) of 60%3-chloroperoxybenzoic acid is added slowly to a solution 0,81 g (1.6 mmole) of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-C]-quinoline in 15 ml of chloroform. The reaction mixture was incubated overnight (about 16 hours), then washed successively with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated to obtain 0.7 g of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)-hexyl]oxy}ethyl)-1H-imidazo[4,5-C]-quinoline-5N-oxide in the form of a solid orange color.

The part With

To a solution of 0.7 g (1.4 mmole) of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)-hexyl]oxy}ethyl)-1H-imidazo[4,5-C]-quinoline-5N-oxide in 20 ml of dichloromethane are added dropwise 0.25 ml (2.1 mmole) try oracleinstance. The reaction mixture was incubated for 2 hours and then added dropwise thereto 2.5 ml of 25%aqueous solution of sodium methylate in methanol, after which the mixture was kept still during the night. The mixture is then subjected to filtration, and the filtrate concentrated. Flash chromatographic purification of the filtrate (silica gel, 97/3 ethyl acetate/methanol) gives 0,22 g of colorless, oily 2-(ethoxymethyl)-1-(2-{[6-(4-phenylmethoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-C]-quinoline-4-amine.

1H NMR(300 MHz, DMSO-d6) δ 8,10 (doublet, J=7.9 Hz, 1H); 7,62 (doublet, J=7.9 Hz, 1H), 7,43 (triplet, J=7,3 Hz, 1H), 7,28-7,12 (multiplet, 6N), 6,55 (singlet, 2H), 4,79 (broad singlet, 4H), 3,82 (triplet, J=5.3 Hz, 2H), 3,55 (Quartet, J=7.0 Hz, 2H), 3.33 and-3,22 (multiplet, 6N), 2,56 (triplet, J=7.2 Hz, 2H), 1,62-1,33 (multiplet, 8H), 1.18 to 1,10 (multiplet, 7H);

MS (El) m/e 518.3263 (518.3256 Calculated for C31H42N4O3);

Analysis. Calculated for C31H42N4O3: %71,78; %N, 8,16; %N, 10,80. Found: %71,20; %N, 8,39; %N, Is 10.68.

Example 21

1-{2-[3-(Benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

A solution of 1.0 g (3.7 mmole) 2-[2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol in N,N-dimethylformamide is added dropwise to a suspension of sodium hydride (0,19 g of 60%suspension in mineral oil, 4.8 mmole) in 20 ml of N,N-dimethylformamide. The mixture was incubated for 2 h the owls and then added dropwise thereto to 0.72 ml (4.1 mmole) benzyl-3-bromopropionic ether. The reaction mixture was stirred at 100°during the night, and then pour it into ice water and extracted with ethyl acetate. Separate organic and aqueous layers. The organic fraction was washed with water, dried over magnesium sulfate and concentrated. The residue is purified by way of flash chromatography (silica gel, eluent is a mixture 4/1 ethyl acetate/hexane) and obtain 0.45 g of 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline as a brown oil.

Using the basic methods used in parts b and C of example 20 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline turn 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine. Purification of the resulting substances by way of flash chromatography (silica gel, 95/5 ethyl acetate/methanol) allows to obtain the target product as a colorless oil.

1H NMR(300 MHz, DMSO-d6) δ 8,11 (double doublet, J=8,2, 0.8 Hz, 1H); 7,62 (double doublet, J=8,3, 1.2 Hz, 1H), 7,44 (double triplet, J=7,6, 1.3 Hz, 1H), 7,30 (doublet, J=8,4 Hz, 2H), 7,21 (double triplet, J=7,6, 1.2 Hz, 1H), 7,32-7,19 (multiplet, 6N), 6,56 (singlet, 2H), 4,85-4,77 (multiplet, 4H), 4.26 deaths (singlet, 2H), 3,84 (triplet, J=5.4 Hz, 2H), 3,54 (Quartet, J=7.0 Hz, 2H), 3,40 (triplet, J=6.2 Hz, 2H), 3,26 (triplet, J=6.2 Hz, 2H), and 1.63 (quintet, J=6.3 Hz, 2H)and 1.15 (triplet, J=7.0 Hz, 3H);

13With NMR (125 MHz, DMSO-d6) δ 152,0, 149,5, 145,2, 138,5, 133,3, 18,1, 127,4, 127,3, 126,8, 126,3, 126,24, 121,0, 120,6, 114,8, 71,8, 69,0, 67,5, 66,3, 65,4, 64,4, 45,4, 29,4, 14,9;

IR-spectrum (KBr tablet): 3305, 3174, 2970, 2925, 2864, 1633, 1583, 1533, 1481, 1437, 1386, 1099, 754, 737, 698 cm-1.

MS (El) m/e 434.2318 (434.2317 Calculated for C25H30N4O3).

Example 22

1-[2-(3-(Phenylpropoxy]ethyl-1H-imidazo[4,5-C]quinoline-4-amine

Part a

In accordance with the basic method used in example 20 (parts a-C), when the interaction of 2-(1H-imidazo[4,5-C]quinoline-1-yl)ethanol (3-bromopropyl)benzene receive 1-[2-(3-(phenylpropoxy]ethyl-1H-imidazo[4,5-C]quinoline-4-amine as a white solid.

1H NMR(300 MHz, DMSO-d6) δ 8.17 (singlet, 1H), 8,12 (doublet, J=7,2 Hz, 1H); to 7.64 (double doublet, J=8,3, 1.0 Hz, 1H), 7,45 (multiplet,1H), 7,24 (multiplet, 1H), 7,16-7,08 (multiplet, 3H), 6,92-6,89 (multiplet, 2H), 6,60 (singlet, 2H), 4,81 (triplet, J=5,1 Hz, 2H), 3,82 (triplet, J=5,1 Hz, 2H), 3,29 (triplet, J=6,1 Hz, 2H), 2,38 (multiplet, 2H), 1,63 (multiplet, 2H), 1.56 to 1,25 (multiplet, 8H), to 0.88 (triplet, J=7.2 Hz, 3H);

13With NMR (75 .CDCl3) δ 151,5, 144,9, 142,6, 141,4, 132,6, 128,3, 128,2, 127,4, 127,1, 125,8, 122,2, 119,8, 115,4, 70,4, 68,6, 47,6, 32,0, 30,9;

MS (El) m/e 347.1882 (347.18 27 Calculated for C21H22N4O).

Example 23

1-(2-{[3-(3,4-Dimetilfenil)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine

In nitrogen atmosphere, 0.5 g (1.9 mmole) of 1-[2-(2-propionyloxy]ethyl-1H-imidazo[4,5-C]-Hino is in-4-amine is added to 0.036 g (0.2 mmole) of copper iodide (I), 0.5 g (2.1 mmole) 4-iodine-ortho-xylene and 10 ml of pyrrolidine and the mixture was stirred at ambient temperature. Type of 0.066 g (0.1 mmole) dichlorobis(triphenylphosphine)palladium (II) and stirring is continued at ambient temperature for 1 hour. Conducted after analysis by the method of thin-layer chromatography for the display use 30%solution of methanol in chloroform) shows the presence in the reaction mixture of the starting material. Therefore, the reaction mixture during the night heated at 65°s Pyrrolidin distilled off under reduced pressure, and the residue is treated with dichloromethane containing methanol. The insoluble product is filtered and recrystallized from toluene (40 ml), resulting in a gain of 0.1 g of solid 1-(2-{[3-(3,4-dimetilfenil)-2-PROPYNYL]oxy}ethyl-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 214-216°C.

Analysis. Calculated for C23H22N4O: %74,57; %N, 5,99; %N, 15,12. Found: %74,24; %N, 5,98; %N, 15,08.

1H NMR(300 MHz, DMSO-d6) δ (ppm) 8,167 (singlet, 1H), 8,49 (singlet, 1H), 8,112 (doublet, J=7,3 Hz, 1H); 7,628 (doublet, J=8,3 Hz, 1H); 7,44 (triplet, J=7,3 Hz, 1H), 7,232 (triplet, J=6,8 Hz, 1H), 7,078 (doublet, J=7.8 Hz, 1H), 7,024 (singlet, 1H); 6,952 (doublet, J=7.9 Hz, 1H), 6,586 (singlet, 2H), 4,849 (triplet, J=5 Hz, 2H), 4,365 (singlet, 2H), 4,015 (triplet, J=5.6 Hz, 2H), 2,197 (singlet, 3H), 2,159 (singlet, 3H).

Examples 24-27/p>

Compounds shown in table 1 are in accordance with scheme 1, using the following primary method of synthesis.

25 mg of 2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)-2-tilateral placed in a vial with a volume of 7.4 ml and add 1.75 equivalents of sodium hydride (60%suspension in mineral oil) and 1 ml of N,N-dimethylformamide. The ampoule is placed for 10 min in an ultrasonic mixing device, and during this time, when the ambient temperature is formed alkoxide. Then to the reaction mixture add 1.75 equivalents of halide and stirring is carried out for 30-60 min at ambient temperature. Conduct mass spectrometric and chromatographic analysis of the reaction mixture to install the formation of the target product. The reaction mixture is purified by way prepreparation high efficient liquid chromatography. Any resulting fraction analyze mass spectrometric method LC-APCI/MS. The appropriate fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and the molecular weight is confirmed using mass spectrometry and spectroscopic. Table 1 shows the structure of the free base, as well as theoretical (TM) and experimentally defined (MM) value is their molecular weight product.

Table 1
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
24AndTM=346.1794 MM=346.1795
25AndTM= 360.1950 MM=360.1955
26AndTM=414.1667 MM=414.1678
27AndTM=424.0899 MM=424.0902

Examples 28-41

Compounds shown in table 2 are in accordance with the scheme of the first process, using the following primary method of synthesis.

25 mg of 4-amino-1H-imidazo[4,5-C]quinoline-1-silt alcohol is placed in a vial with a volume of 7.4 ml and add 1.2 equivalents of sodium hydride (60%suspension in mineral oil) and 1 ml of N,N-dimethylformamide. The ampoule is placed for 1 hour in an ultrasonic mixing device, and during this time at 50°formed alkoxide. Then to the reaction mixture are added 1.2 equivalent of halide and stirring is carried out for 1-2 hours at 50°C. Conduct mass spectrometry the chromatographic analysis of the reaction mixture, to install the formation of the target product. The reaction mixture is purified by way prepreparation high efficient liquid chromatography. Any resulting fraction analyze mass spectrometric method LC-APCI/MS. The appropriate fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and the molecular weight is confirmed using mass spectrometry and spectroscopic. Table 2 shows the structure of the free base, as well as theoretical (TM) and experimentally defined (MM) is the molecular weight of the product.

Table 2
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
28AndTM=394.1794 MM=394.1791
29AndTM=428.1404 MM=428.1396
30AndTM=428.1404 MM=428.1397
31AndTM=408.1950 MM=408.1956

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
32AndTM=408.1950 MM=408.1956
33AndTM=346.1794 MM=346.1791
34AndTM=380.1404 MM=380.1399
35AndTM=380.1404 MM=380.1399

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
36AndTM=360.1950 MM=360.1942
37AndTM=360.1950 MM=360.1941
38AndTM=380.1404 MM=380.1400
39AndTM=371.1746 MM=371.1751

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
40AndTM=380.1404 MM=380.1398
41AndTM=376.1535 MM=376.1536

Examples 42-88

Compounds shown in table 3 is obtained in accordance with scheme 1, using the following primary method of synthesis.

25 mg of 4-amino-1H-imidazo[4,5-C]quinoline-1-silt alcohol is placed in a vial with a volume of 7.4 ml and add 1.2 equivalents of sodium hydride (60%suspension in mineral oil) and 1 ml of N,N-dimethylformamide. The ampoule is placed on 15-30 minutes in an ultrasonic mixing device, and during this time, when the ambient temperature is formed alkoxide. Then to the reaction mixture are added 1.2 equivalent of halide and stirring is carried out additionally for 15-120 minutes at ambient temperature. Conduct mass spectrometric and chromatographic analysis of the reaction mixture to install the formation of the target product. The reaction mixture is purified by way prepreparation high efficient liquid chromatography. Any resulting fraction is analiziruyut mass spectrometric method LC-APCI/MS. The appropriate fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and the molecular weight is confirmed using mass spectrometry and spectroscopic. Table 3 shows the structure of the free base, as well as theoretical (TM) and experimentally defined (MM) is the molecular weight or nominal mass (NM) of the product.

Table 3
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
42AndTM=318.1481 MM=318.1482
43AndTM=328.1535 MM=328.1534
44AndTM=377.1488 MM=377.1487
45AndTM=430.1617 MM=430.1614

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
46 AndTM=371.1746 MM=371.1746
47AndTM=380.1404 MM=380.1394
48AndTM=430.1617 MM=430.1613
49AndTM=360.1950 MM=360.1949

Number exampleThe structure of the free baseWay

cleanup
Molecular weight (daltons)
50AndTM=346.1794 MM=346.1781
51AndTM=363.1331 MM=363.1324
52AndTM=366.1247 MM=366.1243
53AndTM=400.0858 MM=400.0856

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
54 AndTM=364.1331 MM=364.1352
55AndTM=405.1801 MM=405.1794
56AndTM=377.1488 MM=377.1490
57AndTM=391.1644 MM=391.1637

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
58ATM=391.1644 MM=391.1637
59AndTM=360.1950 MM=360.1938
60AndTM=394.1560 MM=394.1558
61AndTM=394.1560 MM=294.1557

Number exampleThe structure of the free and groundsCleaning methodMolecular weight (daltons)
62AndTM=428.1171 MM=428.1159
63AndTM=428.1824 MM=428.1826
64AndTM=385.1903 MM=385.1904
65AndTM=385.1903 MM=385.1897

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
66AndTM=418.2005 MM=418.2013
67AndTM=388.2263 MM=388.2257
68AndTM=400.1511 MM=400.1507
69AndTM=382.1794 MM=382.1788

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
70AndTM=332.1637 MM=332.1641
71img src="https://img.russianpatents.com/850/8506916-s.jpg" height="57" width="55" > AndTM=390.1692 MM=390.1697
72AndTM=346.1794 MM=346.1791
73AndTM=366.1247 MM=366.1241

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
74AndTM=400.1511 MM=400.1512
75AndTM=346.1794 MM=346.1799
76AndTM=360.1950 MM=360.1953

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
77ATM=360.1950 MM=360.1941
78AndTM=414.1667 MM=414.1670
79AndThe m=452 NM[M+H] +1=453

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
80AndTM=360 NM[M+H]+1=361
81AndTM=360 NM[M+H]+1=361
82AndTM=374 NM [M+H]+1=375.2
83InTM=379.1281 MM=379.1278

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
84InTM=348.1586 MM=348.1588
85InTM=362.1743 MM=362.1736
86inTM=362.1743 MM=362.1748

Number exampleThe structure of the NWO is the one Foundation Cleaning methodMolecular weight (daltons)
87InTM=373.1539 MM=373.1546
88InTM=373.1539 MM=373.1543

Examples 89-96

Compounds shown in table 4 are in accordance with the scheme V process, using the following primary method of synthesis.

25 mg of 2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)ethanol was placed in a vial with a volume of 7.4 ml and add 1.2 equivalents of sodium hydride (60%suspension in mineral oil) and 1 ml of N,N-dimethylformamide. The ampoule was placed for 15 minutes in an ultrasonic mixing device, and during this time, when the ambient temperature is formed alkoxide. Then to the reaction mixture are added 1.2 equivalent of halide and stirring is carried out additionally for 15 minutes at ambient temperature. Conduct mass spectrometric and chromatographic analysis of the reaction mixture to install the formation of the target product. The reaction mixture is purified by way prepreparation high efficient liquid chromatography. Any resulting fraction analyze mass spectrometric method LC-APCI/MS. According to dtweedie fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and molecular weight is confirmed using mass spectrometry and spectroscopic. Table 4 shows the structure of the free base, as well as theoretical (TM) and experimentally defined (MM) is the molecular weight of the product.

Table 4
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
89BTM=412.2030 MM=412.2023
90InTM=392.2576 MM=392.2575
91InTM=446.2293 MM=446.2287

In
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
92InTM=446.2293 MM=446.2288
93InTM=403.2372 MM=403.2365
94TM=403.2372 MM=403.2370
95InTM=434.3046 MM=434.3047

Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
96InTM=409.2114 MM=409.2117

Examples 97-100

Compounds shown in table 5 is obtained in accordance with scheme III process, using the following primary method of synthesis.

A portion of the solution volume of 1 ml, obtained by dissolving 0.5 g of 1-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)propan-2-ol in 20 ml of N,N-dimethylformamide, placed in a glass vial with a volume of 7.4 ml, containing 2 equivalents of phenol. In this ampoule add a solution of 54 mg (2 equivalents) of triphenylphosphine in 1 ml of N,N-dimethylformamide. The resulting suspension is exposed to ultrasound to dissolve the phenol, and then to the solution was added 36 mg (2 equivalents) net diethylazodicarboxylate. The reaction mixture was irradiated with ultrasound for 30 minutes and then shaken at ambient temperature overnight. After that, the reaction mixture is purified by way prepreparation high EF the objective liquid chromatography (method A). Target products in examples 99 and 100 is in the form of salts triperoxonane acid. The structure and molecular weight products were confirmed using mass spectrometry and spectroscopic. Table 5 shows the structure of the free base, as well as theoretical value of the molecular weight of the product (TM), and a nominal molecular weight product (NM).

Table 5
Room

example
StructureMolecular weight
97TM=343 NM[M+H]+1=344
98TM=384

NM[M+H]+1=385

Room

example
StructureMolecular weight
99TM=348 NM[M+H]+1=349
100TM=430 NM[M+H]+1=431

Examples 101-104

Compounds shown in table 6 is obtained in accordance with scheme III process, using the following primary method of synthesis.

A portion of the solution volume of 1 ml, the resulting dissolution of the 0.5 g of 2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)-2-tilateral in 20 ml of N,N-dimethylformamide, placed in a vial with a volume of 15 ml containing 2 equivalents of phenol. In this ampoule add a solution of 51 mg (2 equivalents) of triphenylphosphine in 1 ml of N,N-dimethylformamide, and then another, and 34 mg (2 equivalents) net diethylazodicarboxylate. The reaction mixture was irradiated with ultrasound for 2 minutes and then shaken at ambient temperature overnight. Conducted after analysis by high performance liquid chromatography shows that the reaction is not completed. The solvent is removed in vacuum. The obtained oily product was dissolved in 1 ml of tetrahydrofuran containing 2 equivalents of triphenylphosphine, and to the solution was added 2 equivalents net diethylazodicarboxylate. The reaction mixture was shaken at room temperature overnight. According to analysis by the method of liquid chromatography after the reaction is finished completely. The reaction mixture is purified by way prepreparation high efficient liquid chromatography (method B). Any resulting fraction analyze mass spectrometric method LC-APCI/MS. The appropriate fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and the molecular weight is confirmed using mass spectrometry and PMR spectra is roscopy. Table 6 shows the structure of the free base, as well as theoretical value of the molecular weight of the product (TM), and a nominal molecular weight product (NM).

Table 6
Number exampleStructureMolecular weight
101TM=398 NM[M+H]+1=399
102TM=357 NM[M+H]+1=358
103TM=444 NM[M+H]+1=445
104TM=389 NM[M+H]+1=390

Example 105

1-(2-Phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

25 mg (to 0.108 mole) of 2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethanol mixed with 1 ml of N,N-dimethylformamide, to the mixture of 12 mg (0,130 mmole) of phenol and 34 mg (0,130 mmole) of triphenylphosphine and the resulting suspension is irradiated with ultrasound for 1 minute. To the mixture add additional 23 mg (0,130 mmole) of diethylazodicarboxylate and shaking it at ambient temperature for 24 hours. Conducted after analysis by the method of liquid chromatography and mass spectrum is metry (GROMACS analysis) shows the bulk of the original material remained unreacted. To the mixture add additional phenol, triphenylphosphine and diethylazodicarboxylate one equivalent each. The reaction mixture was exposed to ultrasound for 30 minutes After 1 hour according to GROMACS analysis formed the target product. The solvent is removed, and the residue purified by the method prepreparation high-performance liquid chromatography (method A). Data on the molecular weight of the product: TM=304, NM[M+H]+1=305.

Example 106

1-[(1-Phenoxymethyl)propyl]-1H-imidazo[4,5-C]quinoline-4-amine

50 mg (of € 0.195 mmole) of 2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)-2-tilateral mixed with 2 ml of N,N-dimethylformamide, add first 37 mg (0,390 mmole) of phenol and 102 mg of triphenylphosphine, and then 67 mg (0,390 mmole) of diethylazodicarboxylate. The resulting solution was irradiated with ultrasound for 1 hour. Held after that GROMACS analysis shows that the reaction mixture contains the target product and a small amount of starting material. The solvent is removed, and the residue purified by the method prepreparation high-performance liquid chromatography (method A). Measurement of the molecular weight of the product: TM=332, NM[M+H]+1=333.

Example 107

1-{(1R)-1-[(Prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-a is in

Part a

413,8 g (1 equivalent) of crude 4-chloro-3-nitroquinoline dissolved in 1.65 l of dichloromethane. The solution is heated to boiling and filtered through a layer of absorbent Celite®. The filtrate with stirring, cooled to 5°and then add to it one portion 305,4 ml (1.1 equivalents) of triethylamine. The reaction mixture is stirred for 15 minutes, then added dropwise to 250 ml (1.1 equivalents) of (R)-(-)-2-amino-1-butanol, while maintaining the temperature of the reaction mixture not exceeding 40°C. the Mixture was stirred at ambient temperature for several days, then cooled to -30°C. the Resulting yellow precipitate is filtered off, washed with very cold dichloromethane and dried. The solid product is stirred for 1 hour with 1 l of cold mixture of 80/20 water/methanol, filtered off, washed with cold water, washed twice very cold methanol (portions 300 ml) and then dried on the filter overnight. The result is 475 g of (2R)-2-{(3-nitroanilin-4-yl)amino]butane-1-ol.

Part b

238 g of (2R)-2-[(3-nitroanilin-4-yl)amino]butane-1-ol are mixed in a steel vessel with 5 l of isopropanol and 23.8 g of catalyst (activated carbon coated with a 5% platinum) and subjected to hydrogenation at a pressure of 50 lb/in2(3.5 kg/cm2) for 16 hours. Reaction the second mixture is filtered through a layer of absorbent Celite® to remove the catalyst. The filtrate is concentrated under reduced pressure and get of 208.3 g of (2R)-2-[(3-aminoquinoline-4-yl)amino]butane-1-ol in the form of an amber oil. The reaction is repeated a second time in the same conditions.

The part With

416,0 g (1 equivalent) of (2R)-2-[(3-aminoquinoline-4-yl)amino]butane-1-ol is mixed with 1.2 l (4 equivalent) triethylorthoformate and slowly heated to 145°C. the Ethanol formed during the reaction is distilled off. After the volume of distilled ethanol is about 500 ml, the reaction mixture was cooled in a nitrogen atmosphere to 50°C. Excess triethylorthoformate distilled off under reduced pressure and the result of the crude (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol.

Part D

The mixture 434,3 g (2R)-2-(1H-imidazo[4,5-quinoline-1-yl)butane-1-ol and 1.2 l of acetic anhydride slowly for about 2 hours, heated to 100°C. After the reaction, the mixture is left to cool to ambient temperature overnight. To the mixture is added 2.5 l of methanol and heated it up to intense boiling. The reaction mixture is refluxed for 2 hours, cooled to ambient temperature and concentrate under reduced pressure. The residue is diluted with water and then alkalinized it by adding sodium bicarbonate. Analysis by the method of thin layer chromatography (20% methanol in ethyl acetate) showed the t, that the reaction mixture consists of two products and contains no original material. The resulting oil is extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 359,3 g of residue. This material is combined with 1.6 l of acetic anhydride and refluxed for 1 hour. Then the mixture is cooled overnight to ambient temperature and again concentrated under reduced pressure. Analysis by the method of thin-layer chromatography shows the presence of only one spot from the target product. The residue is diluted with 1 l of water, alkalinized her to pH 8 by adding saturated sodium bicarbonate solution, and then stirred for 1 hour. The formed precipitate is filtered off, washed with water and then dried in a vacuum oven overnight at 60°C. the result is solid (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butyl acetate brown.

Part E.

163,0 g (1.1 equivalent) of sodium methylate in the form of a 25%suspension in methanol added in one portion to a solution of 194,0 g (1 equivalent) of (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butyl acetate in 970 ml of methanol. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue is diluted with 1 liter of water, it is realizuyut solution to pH 6-7, adding acetic acid, and then stirred at ambient temperature overnight. The precipitate is filtered off, washed with two portions of water (200 ml each), dried on the filter air and then dried overnight in a vacuum oven at 50°C. the result 145,5 g solid (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol.

Part F

19 g (78,8 mmole) of (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol is added to a mixture of 124 ml of a 50%aqueous solution of sodium hydroxide, 150 ml of dichloromethane, 0.73 g of benzyltrimethylammonium and 11.4 ml (102 mmol) of methyl propargyl. The reaction mixture was stirred at ambient temperature overnight, then dilute it dichloromethane and water. The aqueous fraction is repeatedly extracted with dichloromethane. Organic fraction unite together, washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to purification through column chromatography, using as eluent ethyl acetate. The result of 20.9 g of brown liquid 1-{(1R)-1-[(prop-2-ynyloxy)methyl]-propyl}-1H-imidazo[4,5-C]quinoline.

Part G

To a cooled to 0°With a mixture of material derived in part F, and 250 ml of chloroform added 15.0 g of 57-86%3-chloroperoxybenzoic acid. After 0.5 hours the reaction mixture is heated to a temperature which s environment. Conduct analysis of the reaction mixture by the method of thin-layer chromatography, after which the two portions added 3.75 g of 3-chloroperoxybenzoic acid. Upon completion of the reaction (as judged on the basis of the data analysis method of thin-layer chromatography), the reaction mixture was washed with aqueous sodium bicarbonate solution. The aqueous fraction is extracted with ethyl acetate. Organic fraction unite together, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 1-{(1R)-1-[(propenyloxy)methyl]propyl}-1H-imidazo[4,5-C|quinoline-5N-oxide as a brown oil, which solidified upon standing overnight.

Part N

To a mixture of material derived in part G, and 300 ml of anhydrous dichloromethane is added dropwise to 10.7 ml trichlorotriazine. According to analysis by the method of thin-layer chromatography carried out after 1 hour, the reaction is not completed fully. So add another 2 ml trichlorotriazine. After 1 hour the reaction mixture was concentrated under reduced pressure and get solid 2,2,2-trichloro-N-(1-{(1R)-1-[2-propenyloxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-yl)-ndimethylacetamide in a solid yellow color.

Part I

of 57.5 ml of 25%solution of sodium methylate in methanol is added to a mixture of material derived in part H, and 250 ml of methanol. After 0.5 hours the PE crionna the mixture becomes homogeneous, and it is stirred overnight. The mixture is then concentrated under reduced pressure. The residue is purified on a chromatographic column, using as eluent a mixture of 80/20 dichloromethane/methanol. The obtained solid product was washed with diethyl ether, recrystallized from toluene and dried in an oven at 60°With during the night. In result, you get 9,77 g of crystalline solid 1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine.

1H NMR(300 MHz, DMSO-d6) δ of 8.37 (singlet, 1H), 8,19 (doublet, J=8,3 Hz, 1H), 7,65 (double doublet, J=8,3, 1.5 Hz, 1H), 7,44 (broad triplet, J=7,6 Hz, 1H), 7,25 (broad triplet, J=7,6 Hz, 1H), 6,65 (singlet, 2H), 5,23 (multiplet, 1H), 4,17 (doublet, J=2.0 Hz, 2H), 3,90-4,10 (multiplet, 2H), 3.46 in (triplet, J=2.4 Hz, 1H), 2,07 (multiplet, 2H), from 0.88 (triplet, J=7,3 Hz, 3H).

Example 108

1-((1R)-1-{[(3-Phenylprop-2-inyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

0,80 g (1.25 mmole) of 1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine in the atmosphere of nitrogen is added to 60 ml of anhydrous N,N-dimethylformamide and the mixture is heated to 40°With, then add to it 3,98 g (13.9 mmole) of dibenzyldithiocarbamate. The reaction course is monitored using the method of thin-layer chromatography and high performance liquid chromatography.

2 hours to the mixture add 1 g of dibenzylidene the and. After 1 hour, then the reaction is finished. The reaction mixture was diluted with ethyl acetate, washed first with water and then brine, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain N,N-(bis-benzyloxycarbonyl)-1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine as light brown oil. This oil was washed with hexane to remove excess dibenzyldithiocarbamate.

Part b

The mixture 1,91 g (3.4 mmole) of N,N-(bis-benzyloxycarbonyl)-1-{(1R)-1-[(prop-2-inyl-hydroxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine, 30 ml of anhydrous acetonitrile and 0.71 ml (5.1 mmole) of triethylamine is heated to 70°and to this mixture was 0.026 g of copper iodide (I), 0,048 g dichlorobis(triphenylphosphine)palladium (II) and 0.40 ml (3.7 mmole) of odensala. The reaction is terminated after 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed first with water and then brine, dried over magnesium sulfate, filtered and concentrated under ponizhennom pressure to obtain a brown liquid. This material is purified on a chromatographic column, using as eluent a mixture of 39.5/59,5/1 ethyl acetate/hexane/triethylamine, and the result is 2.1 g of oily product, which is a mixture of mono - and desasosiego benzyloxycarbonylamino groups 1-((1R)-1-{[(3-phenylprop-2-inyl)oxy)methyl]propyl}-1H-imidazo[45-a]quinoline-4-amine.

The part With

Part of the material (0.8 g)obtained in stage B, is mixed with methanol and 1.0 ml of 25%solution of sodium methylate in methanol. After 16 hours the reaction according to the analysis by the method of thin-layer chromatography is completed. The reaction mixture was concentrated under reduced pressure. The resulting oil is purified on a chromatographic column, elwira product a 5%solution of methanol in dichloromethane. Obtained at this stage glassy substance is dried overnight in high vacuum at ambient temperature and obtain 0.3 g of 1-((1R)-1-{[(3-phenylprop-2-inyl)oxy]methyl}propyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 63-67°C.

Analysis. Calculated for C23H22N4O: %74,57; %N, 5,99; %N, 15,12. Found: %74,18;%N,6,10;%M 15,00.

1H NMR(300 MHz, DMSO-d6) δ 8,40 (singlet, 1H), 8,21 (doublet, J=8,3 Hz, 1H), to 7.64 (double doublet, J=8,5, 1.2 Hz, 1H), 7,43 (broad triplet, J=7,6 Hz, 1H), 7,25-7,40 (multiplet, 5H), 7,22 (broad triplet, J=7,6 Hz, 1H), 6,61 (singlet, 2H), 5,26 (multiplet, 1H), to 4.41 (singlet, 2H), 3.95 to 4,20 (multiplet, 2H), 2,10 (multiplet, 2H), 0,90 (triplet, J=7,3 Hz, 3H).

IR-spectrum (KBr tablet): 3306, 1634, 1526,1100, cm-1.

HRMS(EI) Calculated for C23H22N4O (M+) 370,1794 found 370,1798.

Example 109

1-{(1R)-1-[(3-Phenylpropoxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine

0,72 g of palladium hydroxide (20%of product deposited on activated carbon) in the atmosphere of nitrogen are added to a solution of 1.3 g of the material obtained in part b of example 108, approximately 20 ml of methanol. The mixture hydronaut at a pressure of 50 lb/in2(3.5 kg/cm2) for 3.5 hours. Then the catalyst is filtered off. The filtrate is concentrated under reduced pressure. After purification of the residue by chromatographic column using as eluent a 2.5%solution of methanol in dichloromethane get oily product. This product is treated with diethyl ether, the resulting solid product is separated and dried. The result is 0.4 g of white crystalline solid 1-{(1R)-1-[(3-phenylpropoxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 118-120°C.

Analysis. Calculated for C23H26N4O: %73,77; %N, 7,00; %N, 14,96. Found: %73,68; %H, 7.17; %N, 14,72.

1H NMR(300 MHz, DMSO-d6) δ 8,39 (singlet, 1H), they were 8.22 (doublet, J=7.8 Hz, 1H), 7,65 (double doublet, J=8,3, 1.0 Hz, 1 H), 7,43 (broad triplet, J=7,6 Hz, 1 H), 7,25-7,40 (multiplet, 5H), 7,44 (broad triplet, J=7.7 Hz, 1H), 7,05-7,30 (multiplet, 4H), to 6.95 (broad doublet, J=6,8 Hz, 2H), 6,62 (singlet, 2H), 5,20 (multiplet, 1H), 3,88 (multiplet, 2H), 3,36 (multiplet, 2H), 2,37 (broad triplet, J=7,6 Hz, 2H), 2,08 (multiplet, 2H), 1,63 (multiplet, 2H), 0,8 (triplet, J=7,3 Hz, 3H).

IR-spectrum (KBr tablet): 3458, 3109, 1639, 1528, 1392, 1250, cm-1.

HRMS(EI) Calculated for C23H26N4O (M+) 374,2107 found 374,2104.

Examples 110-112

Part a

15 ml of triethylamine and about 0.1 mole of the crude R-3-amino-2-methylpropan-1-ol are added to a solution of 24.3 g (0.1 mol) of 2,4-dichloro-3-nitroquinoline in 250 ml of dichloromethane. The reaction mixture is refluxed until, while, according to thin-layer chromatography of the reaction mixture does not cease to change. After that, the mixture is evaporated to dryness. Solid yellow-brown residue is ground and to remove residual source quinoline extracted several times with hexane containing a small amount of dichloromethane. The residue is recrystallized from isopropanol and get 19,0 g yellow solid R-3-[(2-chloro-3-nitroanilin-4-yl)amino]-2-methylpropan-1-ol. 500 mg of this product again recrystallized from isopropanol and as a result receives a yellow solid crystalline substance, melting point which is 174-176°C.

Part b

A mixture of 10 g (33.8 mmole) of R-3-[(2-chloro-3-nitroanilin-4-yl)amino]-2-methylpropan-1-ol, 350 ml of isopropanol and about 1 g of catalyst (activated carbon coated with a 5% platinum) is subjected to hydrogenation in a Parr apparatus at an initial hydrogen pressure of 50 lb/in2 (3.5 kg/cm2). After cessation of hydrogen absorption, the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated under reduced pressure to obtain the crude R-3-[(3-amino-2-chlorhydrin-4-yl)amino]-2-methylpropan-1-ol. To this crude intermediate product add 10.0 ml (61.5 mmole) of diethoxymethylsilane. The result is a reaction, accompanied by strong heating. The resulting solution is heated on the steam bath for 20 minutes and then the reaction mixture was diluted with water and ammonium hydroxide. The obtained oily product is extracted with ethyl acetate. Extracts combine together, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid is mixed with a mixture of ethyl acetate/hexane, filtered off, washed with a mixture of ethyl acetate/hexane and dried. The result is 6.0 g reddish/yellow solid R-3-(4-chloro-1H-imidazo[4,5-C]quinoline-1-yl)amino]-2-methyl-propan-1-ol.

The part With

1.0 g (3.6 mmole) of R-3-(4-chloro-1H-imidazo[4,5-C]quinoline-1-yl)amino]-2-methyl-propan-1-ol and 30 ml of 15%methanolic solution of ammonia is heated in a steel autoclave at 150°C. After a certain time the reaction vessel is cooled to ambient temperature. To the reaction mixture an excess of methanolic solution of sodium hydroxide, and then see the camping concentrated under reduced pressure to obtain the desired volume of the mixture. To the residue water is added and the concentration continue to obtain a solid product. This product is filtered, washed with water and dried, resulting in a gain white solid. This material is recrystallized from methanol/dichloromethane and receive a colorless solid R-3-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)-2-methylpropan-1-ol, melting point which is 258-261°C.

Analysis. Calculated for C14H16N4ABOUT: %65,61; %N, 6,29; %N, 21,86. Found: %65,50; %N, And 6.3; %N, 21,7.

Part D

Compounds shown in table 7 are in accordance with the scheme of the first process, using the following primary method of synthesis.

25 mg of R-3-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)-2-methylpropan-1-ol was placed in a vial with a volume of 7.4 ml and add 1.2 equivalents of sodium hydride (60%suspension in mineral oil) and 1 ml of N,N-dimethylformamide. The ampoule was placed in an ultrasonic mixing device and irradiated with ultrasound at 50°C for 15 minutes. During this time, the formation of alkoxide. Then to the reaction mixture are added 1.2 equivalent of halide and stirring in an ultrasonic mixing device is carried out for 2 hours at 50°C. Conduct mass spectrometric and chromatographic analysis of the reaction mixture to set education Zell is on the product. Reaktsionnuyu the mixture is purified by way prepreparation high efficient liquid chromatography. Any resulting fraction analyze mass spectrometric method LC-APCI/MS. The appropriate fractions are combined together and subjected to lyophilization to obtain triperoxonane salt of the desired product, the structure and the molecular weight is confirmed using mass spectrometry and spectroscopic. Table 7 shows the structure of the free base, as well as theoretical (TM) and experimentally defined (MM) is the molecular weight of the product.

Table 7
Number exampleThe structure of the free baseCleaning methodMolecular weight (daltons)
110AndTM=371.1746 MM=371.1749
111AndTM=402.2420 MM=402.2413
112AndTM=380.1404 MM=380.1402

Example 113

1-[(Benzyloxy)methyl]-1H-imidazo[4,5-c]quinoline-4-amine

of 0.48 g (11.9 mmole) of 60%suspension hydride intothree the mineral oil is added to a suspension of 2.0 g (10.9 mmole) of 1H-imidazo[4,5-C]quinoline-4-amine in N,N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 3 hours, then cooled in an ice bath and add 1.5 ml (up 10.9 mmole) benzylchloride ether. The mixture was stirred at ambient temperature for 2 hours, then heated on a steam bath for 1 hour. The formed precipitate is filtered off. The filtrate is diluted with water and the separated oil phase. The oil is mixed with the precipitate and obtain 2.1 g of adhesive solids. This substance is treated with 5 ml of boiling ethyl acetate. The mixture is cooled and the precipitate filtered off. The filtrate is concentrated under reduced pressure. The resulting residue is twice treated with ethyl acetate and then added to the previously obtained precipitate, resulting in a gain of 0.8 g of solid product. After recrystallization of this product from approximately 5 ml of ethanol and 0.6 g of 1-[(benzyloxy)methyl]-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 168-172°C.

Analysis. Calculated for C18H16N4O: %C 71,0; %N, WITH 5.3; %N, 18,4. Found: %70,9; %N, With 5.3; %N, 18,4.

Example 114

1-(2-{3-[4-(Dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 12, part a, 2.5 g (are 5.36 mmole) of N,N-(bis-tert-butoxycarbonyl)-1-[2-(2-propenyloxy)ethyl]-1H-and is idazo[4,5-C]quinoline-4-amine is treated at 70° With a 1.46 g (of 5.89 mmole) 4-iodine-N,N-dimethylaniline. The reaction is completed within 30 minutes. The solution is diluted with ethyl acetate, washed three times with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The remaining solid product was then purified chromatographically on silica gel, using as eluent a mixture 98/2 dichloromethane/methanol, and the result is 0,883 g brown solid tert-butyl-1-[2-({3-[4-(dimethylamino)phenyl]prop-2-inyl}oxy)ethyl]-1H-imidazo-[4,5-C]quinoline-4-ylcarbamate.

MS(Cl) for C33H39N5O5m/z 586 (MH+), 486, 386, 229.

Part b

Using the primary method used in example 12, part b, carry out the hydrogenation 0,883 g (1,507 mmole) of tert-butyl-1-[2-({3-[4-(dimethylamino)phenyl]prop-2-inyl}oxy)ethyl]-1H-imidazo[4,5-C]-quinoline-4-ylcarbamate, resulting in a gain 0,783 g brown solid tert-butyl-1-[2-{3-[4-(dimethylamino)phenyl]propoxy}-ethyl]-1H-imidazo[4,5-C]quinoline-4-ylcarbamate.

MS(Cl) for C33H43N5O5m/z 590 (MN+), 490, 390, 229.

The part With

Using the primary method used in example 12, part With, carry out a reaction between 0,783 g (1,327 mmole) of tert-butyl-1-[2-{3-[4-(dimethylamino)phenyl]propoxy}ethyl]-1H-imidazo[4,5-C]quinoline-4-ylcarbamate and 10 ml triperoxonane acid. Received the product on the every treated with ethyl ether and the result 0,634 g of a white solid salt triperoxonane acid: (1-(2-{3-[4-(dimethylamino)phenyl]propoxy}-ethyl]-1H-imidazo-[4,5-C]quinoline-4-amine).(triptorelin)of 1.5. The melting point of this product is 137-140°C.

Analysis. Calculated for C23H27N5O.(C2HF3O2)1,5: %C 54,83; %N, 5,22; %N, 12,30. Found: %C 54,67; %N, 4,91; %N, 12,27.

1H NMR(300 MHz, DMSO-d6) δ 9,04-9,11 (broad singlet, 2H), 8,49 (singlet, 1H), at 8.36 (doublet, J=7,3 Hz, 1H), 7,83 (doublet, J=8,3 Hz, 1H), 7,74 (triplet, J=8,3 Hz, 1H), 7,56 (triplet, J=6,8 Hz, 1H), of 6.71 (doublet, J=7.8 Hz, 2H), 6,60 (multiplet, 2H), 4,90 (triplet, J=4,9 Hz, 2H), 3,83 (triplet, J=4,9 Hz, 2H), 3.27 to (triplet, J=5,9 Hz, 2H), 2,28 (singlet, 6N), 2,25 (triplet, J=7.8 Hz, 2H), and 1.54 (quintet, J=6,4, 6,8, 2N)

MS(Cl) for C23H27N5O m/z 390 (MH+), 229.

Example 115

1-(2-{[(2E)-3-Phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

In a dry round-bottom flask equipped with a magnetic stirrer, under nitrogen atmosphere download 0,19 g (4,65 mmole) of 60%suspension of sodium hydride in mineral oil and 2 ml of hexane. Then with a syringe into the flask, add 10 ml of anhydrous dimethylformamide and 0,902 g (to 4.23 mmole) of 2-(1H-imidazo[4,5-C]quinoline-1-yl)ethanol, and the mixture is heated at 60°C for 20 minutes. After this time the solution with a syringe type of 0.65 ml (4,65 mmole) of the acid chloride of cinnamic acid. After 50 minutes the yield of the target product is approximately 80%. Volatile products are distilled off under reduced pressure and obrotowe the Xia oil partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane; the organic fraction unite together, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting glassy product is subjected to chromatographic purification on silica gel using as eluent a mixture of 95/5 dichloromethane/methanol) and dried in a vacuum oven at 60°C for 15 hours. The result 0,652 g of 1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline in the form of a glassy solid product.

MS(Cl) for C21H19N3O m/z 330 (MH+), 214.

Part b

Using the primary method used in example 1, part b, 0,652 g (1.98 mmole) 1-(2-{[(2B)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline oxidizes to 0.67 g of 1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide. This brown solid used without further purification.

The part With

In a round bottom flask, equipped with a magnetic stirrer at ambient temperature load of 0.67 g (1.98 mmole) 1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide, 15 ml of dichloromethane and 7 ml of a 27%aqueous ammonium hydroxide solution. To the mixture in several portions add 0,415 g (2.18 mmole) of solid n-toluensulfonate and the resulting solution is stirred. The reaction is finished within 20 minutes; p is the target partitioned between water and organic phases. The aqueous layer was extracted three times with dichloromethane. Organic fraction unite together, shaken out three times with 5%aqueous sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting white solid is recrystallized five times from methanol/water and the result is 0,086 g of 1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine as a white fluffy product. The melting point of this product is 183,7-184,3°C.

Analysis. Calculated for C21H20N4O: %73,23; %N, 5,85; %N, 16,27. Found: %73,11;%N, 5,81 ;%N, 16,10.

1H NMR(300 MHz, DMSO-d6) δ 8,19 (singlet, 1H), 8,12 (doublet, J=7,3 Hz, 1H), 7.62mm (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=8,3 Hz, 1H), 7,19-7,31 (multiplet, 6N), 6,61 (singlet, 2H), 6,33 (doublet, J=15.6 Hz, 1H), 6,17 (double triplet, J=16,0, 5,2 Hz, 1 H), 4,84 (triplet, J=4,9 Hz 2N). 4,07 (triplet, J=3,9 Hz, 2H), 3,91 (triplet, J=5.4 Hz, 2H)

MS(Cl) for C21H20N4O m/z 345 (MN+), 270, 229.

Example 116

2-Octyl-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 1, part a, conduct the reaction between 4.8 g (14,75 mmole) of 2-(2-octyl-1H-imidazo[4,5-C]quinoline-1-yl)ethanol and methyl-propargyl (in the form of an 80%aqueous solution of the toluene) (4,93 ml, 44,25 mmole), as a result 4,84 g brown solid product - 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline.

Part b

Using the main method of synthesis used in example 12, part a, 4,84 g (13,32 mmole) 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline at 40°treated With 1.7 ml (14,65 mmole) of odensala. The reaction is completed within 45 minutes. Volatile products are removed under reduced pressure, and the remaining oily product is subjected to chromatographic purification on silica gel (eluent a mixture 98/2 dihormati/methanol). After treatment, get to 4.2 g of a pale yellow solid 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C29H33N3About m/z 440 (MN+), 291.

The part With

Using the primary method used in example 1, part b, 2.2 g (5,004 mmole) 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline oxidizes to 2.28 g of 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide, which represents an oily product.

Part D

Using the primary method used in example 115, part With, spend amination 2,22 g (a 4.83 mmole) 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide. Formed as a result of this reaction, the solid brown product processed is t diethyl ether and recrystallized from 2-propanol, which leads to the obtaining of 1.23 g of 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine as a white crystalline solid. The melting point of this product is 138-138,7°C.

Analysis. Calculated for C29H34N4ABOUT: %76,62; %N, 7,54; %N, 12,32. Found: %76,6; %N, 7,49; %N, 12,19.

1H NMR(300 MHz, DMSO-d6) δ 8,07 (doublet, J=8,3 Hz, 1H), 7.62mm (doublet, J=8,3 Hz, 1H), 7,41 (triplet, J=6,8 Hz, 1H), 7,27 was 7.36 (multiplet, 3H), 7.18 in-7,24 (multiplet, 3H), 6,45 (singlet, 2H), 4,78 (triplet, J=4,9 Hz, 2H), 4,34 (singlet, 2H), 4.00 points (triplet, J=4,9 Hz, 2H), 2,94 (triplet, J=7.8 Hz, 2H)and 1.83 (quintet, J=7,3, 7,3 Hz, 2H), 1,22-1,43 (multiplet, 10H), 0,85 (triplet, J=6,8 Hz, 3H)

MS(Cl) for C29H34N4O m/z 455 (MN+), 283.

Example 117

2-Octyl-1-[2-(3-phenylpropoxy)ethyl])-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 12, part b, carry out the hydrogenation of 2-octyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline (2.0 g, 4,55 mmole) and 2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline (1.78 g), a white solid product.

1H NMR(300 MHz, DMSO-d6) δ 9,15 (singlet, 1H), to 8.41 (doublet, J=9,78 Hz, 1H), 8,16 (doublet, J=9.8 Hz, 1H), 7,63-7,71 (multiplet, 2H), 7,06-7,09 (multiplet, 3H), for 6.81-6,84 (multiplet, 2H), 4,85 (triplet, J=4,9 Hz, 2H), 3,84 (triplet, J=4,9 Hz, 2H), 3,25 (triplet, J=4,9 Hz, 2H), 3.04 from (triplet, J=7.8 Hz, 2H), 2,31 (triplet, J=8,3 Hz, 2H), at 1.91 (quintet, J=7,3, 7,3 Hz, 2H), equal to 1.59 (quintet, J=8,8, 5.8 Hz, 2H), 1,25-1,49 (multiplet, 10H), 0,85 (triplet, J=7,3 Hz, 3H).

Part b

Using the primary method used in example 1, part b, 1.78 g (a 4.03 mmole) 2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline oxidizes to 1.8 g of oily 2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide.

The part With

Using the primary method used in example 115, part With, spend amination of 1.85 g (a 4.03 mmole) 2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown solid product is treated with diethyl ether and recrystallized from acetonitrile, which leads to obtain 0.31 g of 2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine as a white crystalline solid. The melting point of this product is to 103.8-104,5°C.

Analysis. Calculated for C29H38N4O: %75,94; %N, 8,35; %N, 12,22. Found: %75,71; %N, 8,46; %N, 12,22.

1H NMR(300 MHz, DMSO-d6) δ 8,06 (doublet, J=7.8 Hz, 1H), 7.62mm (doublet, J=8,3 Hz, 1H), 7.41 (triplet, J=7.8 Hz, 1H), 7,21 (triplet, J=7.8 Hz, 1H), 7,05-7,15 (multiplet, 3H), 6.90 to (double doublet, J=5,4, 1.9 Hz, 2H), 6,45 (singlet, 2H), 4,73 (triplet, J=4.4 Hz, 2H), 3,80 (triplet, J=4,9 Hz, 2H), 3,24 (triplet, J=5,9 Hz, 2H), 2,97 (triplet, J=7.8 Hz, 2H), 2,39 (triplet, J=7.8 Hz, 2H), of 1.85(quintet, J=7,3, 7,8 Hz, 2H), of 1.62 (quintet, J=6,8, and 6.3 Hz, 2H), 1,22-1,44 (multiplet, 10H), 0.84 (triplet, J=6,8 Hz, 3H)

MS(Cl) for C29H38N4O m/z 459 (MN+), 373, 285.

Example 118

2-Methyl-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 1, part a, conduct the reaction between 4.0 g (to 17.6 mmole) of 2-(2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)ethanol and methyl-propargyl (80%solution in toluene) (5,9 ml, 52,8 mmole), as a result of 3.6 g of a dark brown oily product is 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-}quinoline.

MS(Cl) for C16H15N3About m/z 266 (MH+), 184.

Part b

Using the primary method used in example 12, part a, 3.6 g (13,57 mmole) of 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline process at an ambient temperature of 1.7 ml (14,92 mmole) of odensala. The reaction is finished after 20 hours. The solution is alkalinized by adding 5%aqueous sodium bicarbonate solution, and then extracted three times with dichloromethane. The organic fractions are combined together, washed three times with water and then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. For final purification of the product is passed through silica gel (quality is as eluent a mixture of 95/5 dichloromethane/methanol) and recrystallized from acetonitrile. The result of 1.94 g of light yellow solid 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C22H19N3About m/z 342 (MH+), 228.

The part With

Using the primary method used in example 1, part b, 1.0 g (of 2.93 mmole) of 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline oxidized to obtain 1.3 g of 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide, representing a reddish solid.

1H NMR(300 MHz, DMSO-d6) δ 8,94 (singlet, 1H), 8,78 (doublet, J 8,3 Hz, 1H), 8,48 (doublet. J=7.8 Hz, 1H), 7,79 (multiplet, 2H), 7,26-7,35 (multiplet, 3H), 7,09-7,18 (multiplet, 2H), 4,86 (triplet, J=5.4 Hz, 2H), 4,34 (singlet, 2H), 4.04 the (triplet, J=4,9 Hz, 2H), 2,66 (singlet, 3H).

Part D

Using the primary method used in example 115, part With, spend amination of 1.05 g (of 2.93 mmole) of 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide. Formed during this reaction the solid reddish product is treated with diethyl ether and recrystallized from toluene, and then subjected to chromatographic purification on silica gel using as eluent a mixture 98/2 dichloromethane/methanol). The result 0,261 g 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine as a white crystalline solid. Temperature is Lavinia this product is 142,7-br143.3° C.

Analysis. Calculated for C22H20N4O: %74,14; %N, 5,66; %N, 15,72. Found: %73,97; %N, 5,77; %N, 15,77.

1H NMR(300 MHz, DMSO-d6) δ 8,08 (doublet, J=8,3 Hz, 1H), to 7.61 (doublet, J=8,3 Hz, 1H), 7,41 (triplet, J=8,3 Hz, 1H), 7,28-7,35 (multiplet, 3H), 7,12-7,24 (multiplet, 3H), 6,52 (singlet, 2H), 4,77 (triplet, J=4,9 Hz, 2H), 4,36 (singlet, 2H), was 4.02 (triplet, J=4,9 Hz, 2H), 2,62 (singlet, 3H)

MS(Cl) for C22H20N4O m/z 357 (MN+), 243, 199.

Example 119

2-Methyl-1-[2-(3-phenylpropoxy)ethyl])-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 12, part b, carry out the hydrogenation of 2-methyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]-quinoline (0.9 g, 2,636 mmole) of 2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline (0,845 g), a white solid product.

1H NMR(300 MHz, DMSO-d6) δ 9,12 (singlet, 1H), 8,44 (doublet, J=7,3 Hz, 1H), 8,16 (doublet, J=7.8 Hz, 1H), 7,65-7,70 (multiplet, 2H),? 7.04 baby mortality-7,08 (multiplet, 3H), 6,79-6,83 (multiplet, 2H), 4,85 (triplet, J=4,9 Hz, 2H), 3,85 (triplet, J=5.4 Hz, 2H), 3,23 (triplet, J=6,4 Hz, 2H), 2,70 (singlet, 3H), 2,3 (triplet, J=7.8 Hz, 2H), 1,58 (quintet, J=6,36, 6,36 Hz, 2H).

Part b

Using the primary method used in example 1, part b, 0,845 g (of 2.45 mmole) of 2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline oxidizes to 0.88 g of 2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]Hino is in-5N-oxide, representing a hard glassy substance. This product is further used without additional purification.

The part With

Using the primary method used in example 115, part With, spend amination of 0.88 g (of 2.45 mmole) of 2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown solid product is treated with diethyl ether and recrystallized from toluene, resulting in 0,596 g 2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine as a white powder. The melting point of this product is 129,7-130,7°C.

Analysis. Calculated for C22H24N4O: %73,31; %N, OF 6.71; %N, 15,54. Found: %73,21 ;%N, 6,66; %N, 15,58.

1H NMR(300 MHz, DMSO-d6) δ 8,07 (doublet, J=8,3 Hz, 1H), 7.62mm (doublet, J=7,3 Hz, 1H), 7,41 (triplet, J=7,3 Hz, 1H), 7,22 (triplet, J=8,3 Hz, 1H), 7,05-7,14 (multiplet, 3H), 6,88 (double doublet, J=6,8, 2.4 Hz, 2H), 6,52 (singlet, 2H), 4,73 (triplet, J=4,9 Hz, 2H), 3,80 (triplet, J=4,9 Hz, 2H), 3,24 (triplet, J=6,4 Hz, 2H), 2,64 (singlet, 3H), 2,38 (triplet, J=8,3 Hz, 2H), of 1.62 (quintet, J=6.8 cm, 6.4 Hz, 2H)

MS(Cl) for C22H24N4O m/z 361 (MN+), 347, 199.

Example 120

2-(Methoxyethyl)-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amine

Part a

Using the primary method used in example 1, conduct the reaction m is waiting for 2,53 g (was 9.33 mmole) 2-[2-(methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol and methyl-propargyl (80%solution in toluene) (3,11 ml, of 27.9 mmole), as a result of 2.72 g of the oily product is 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C18H19N3O2m/z 310 (MH+), 278, 196.

Part b

Using the primary method used in example 12, part a, of 2.72 g (1,79 mmole) of 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline treated at ambient temperature with 1.1 ml (9,67 mmole) of odensala. The reaction is finished after 45 minutes. Volatile products are distilled off under reduced pressure and the remaining oily product partitioned between dichloromethane and 5%aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The organic fractions are combined together, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown solid product. This product is subjected to chromatographic purification on silica gel (eluent is a mixture of 95/5 dichloromethane/methanol) and treated with hexane. The result 2,39 g yellow solid 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C24H23N3O2m/z 386 (MN+), 354, 270.

The part With

Using the primary method used in example 1, part b, 1.19 g (3,097 mmole) of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-it is dazo[4,5-C]quinoline oxidized to obtain 1.24 g of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide, representing a glassy solid.

Part D

Using the primary method used in example 115, part With, spend amination 1,243 g (3,097 mmole) of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown oily product is subjected to chromatographic purification on silica gel using as eluent a mixture 98/2 dichloromethane/methanol) and recrystallized from ethyl acetate and acetonitrile, resulting in 0,379 g of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine as a white crystalline solid substance. The melting point of this product is 134,5-135,5°C.

Analysis. Calculated for C24H24N4O2: %71,98; %N, 6,04; %N, 13,99. Found: %72,21; %N, 5,98; %N, 14,29.

1H NMR(300 MHz, DMSO-d6) δ 8,09 (doublet, J=8,3 Hz, 1H), 7.62mm (doublet, J=8,3 Hz, 1H), 7,41 (triplet, J=8,3 Hz, 1H), 7,28-7,35 (multiplet, 3H), 7.18 in-7,24 (multiplet, 3H), 6,50 (singlet, 2H), 4,82 (triplet, J=4,9 Hz, 2H), 4,36 (singlet, 2H), 4,01 (triplet, J=4,9 Hz, 2H), 3,84 (triplet, J=6,8 Hz, 2H), 3,29 (singlet, 3H), 3,23 (triplet, J=6,8 Hz, 2H),

MS(Cl) for C24H24N4O2m/z : 401 (MH+), 255, 183.

Example 121

2-(2-Methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl])-1H-imidazo[4,5-C]quinoline-4-amine

Part a

is using the main method, used in example 12, part b, carry out the hydrogenation of 2-(2-methoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]-quinoline (1.2 g, 3.11 mmole) 2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline (1.01 g), an oily product.

MS(Cl) for C24H27N3O2m/z 390 (MH+), 235.

Part b

Using the primary method used in example 1, part b, 1.01 g (2,60 mmole) of 2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline oxidizes to 1.05 g of 2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide, which represents an oily product.

The part With

Using the primary method used in example 115, part With, spend amination of 1.05 g (2,601 mmole) of 2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown solid product is subjected to chromatographic purification on silica gel using as eluent a mixture 98/2 dichloromethane/methanol) and recrystallized from a mixture of ethyl acetate/hexane and the result 0,111 g of white solid 2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is to 103.8-104,5°C.

Analysis. Calculated for C24H28N4O2.(H2O)of 0.2: %C BR70.63; %N 7,01; %N, 13,73. Found: %C 70,38; %N, 6,80; %N, 13,57.

1H NMR(300 MHz, DMSO-d6) δ 8,09 (doublet, J=7,3 Hz, 1H), 7,63 (doublet, J=8,3 Hz, 1H), 7,42 (triplet, J=6,8 Hz, 1H), 7,22 (triplet, J=7.8 Hz, 1H), 7,08-7,15 (multiplet, 3H), 6.89 in (doublet, J=5.4 Hz, 2H), of 6.49 (singlet, 2H), 4,78 (triplet, J=4,9 Hz, 2H), 3,86 (triplet, J=6,8 Hz, 2H), 3,80 (triplet, J=5.4 Hz, 2H), 3,30 (singlet, 3H), 3,22 of 3.28 (multiplet, 4H), 2,39 (triplet, J=8,3 Hz, 2H), of 1.62 (quintet, J=8,3, 6.4 Hz, 2H)

MS(Cl) for C24H28N4O2m/z 405 (MH+), 373, 235.

Example 122

2-(Ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amine

Part a

Using the primary method used in example 1, part a, conduct the reaction between 1.39 g (5,123 mmole) 2-[2-(ethoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol and methyl-propargyl (80%solution in toluene) (1.7 ml, shed 15.37 mmole), as a result of 1.6 g of the oily product is 2-(ethoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C18H19N3O2m/z 310 (MH+), 371, 270.

Part b

Using the primary method used in example 12, part a, 1.5 g (4,13 mmole) of 2-(ethoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline treated at 40°odensala (0.51 ml, 4.54 mmole). The reaction is completed within 50 minutes. Volatile products are distilled off under reduced pressure and the remaining oily p is oduct partitioned between dichloromethane and 5%aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The organic fractions are combined together, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily product. This product is subjected to chromatographic purification on silica gel (eluent is a mixture of 95/5 dichloromethane/methanol) and the result of 1.25 g of a brown glassy solid of 2-(ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C24H23N3O2m/z 386 (MH+), 342, 272.

The part With

Using the primary method used in example 1, part b, oxidize 0,655 g (1,70 mmole) of 2-(ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-quinoline and gain of 0.68 g of oily 2-(ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide.

Part D

Using the primary method used in example 115, part With, spend amination 0,682 g (1,700 mmole) of 2-(ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown solid product is subjected to chromatographic purification on silica gel using as eluent a mixture 98/2 dichloromethane/methanol), resulting in 0,297 g of 2-(ethoxyethyl)-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine as white is granulirovannogo solids. The melting point of this product is 110,8-111,7°C.

Analysis. Calculated for C24H24N4O2.(H2O)a 0.1: %C 71,66; %N, 6,06; %N, 13,93. Found: %C 71,56; %N, 5,96; %N, 13,74.

1H NMR(300 MHz, DMSO-d6) δ 8,13 (doublet, J=7.8 Hz, 1H), 7,63 (doublet, J=8,3 Hz, 1H), 7,44 (triplet, J=6,8 Hz, 1H), 7,28 and 7.36 (multiplet, 3H), 7,19-7,26 (multiplet, 3H), 6,67 (singlet, 2H), 4,88 (triplet, J=5.4 Hz, 2H), to 4.38 (singlet, 2H), 4,03 (triplet, J=5,9 Hz, 2H), 3,55 (quintet, J=6,8, and 7.3 Hz, 2H)and 1.15 (triplet, J=6,8 Hz, 3H)

Example 123

2-Butyl-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 1, part a, conduct the reaction between 5.0 g (18,56 mmole) of 2-(2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethanol and methyl-propargyl (80%solution in toluene) (6.3 ml, 55,62 mmole), and as a result was 4.02 g of solid yellowish-brown product is 2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C19H21N3O m/z 308 (MH+), 268, 220.

Part b

Using the primary method used in example 12, part a, 4.0 g (13,08 mmole) of 2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-quinoline at 90°treated With 1.6 ml (14,38 mmole) of odensala. The reaction is complete within 15 minutes. Volatile products are removed under reduced pressure, and the remaining oily PR the product is subjected to chromatographic purification on silica gel (eluent a mixture 98/2 dichloromethane/methanol), and then recrystallized from a mixture of ethyl acetate/hexane. After cleaning get 3.1 g of a yellowish-brown solid 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline.

The part With

Using the primary method used in example 1, part b, 1.0 g (2,61 mmole) of 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline oxidizes to 1.0 g of oily 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide.

Part D

Using the primary method used in example 115, part With, spend amination of 1.04 g (2,60 mmole) of 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-5N-oxide. Resulting from this reaction brown solid product is treated with diethyl ether, then twice subjected to chromatographic purification on silica gel, using as eluent first mixture 8/2 dichloromethane/ethyl acetate, and then the mixture 98/2 dichloromethane/methanol. As a result, the stonecrops get 0,450 g of 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine as a white powder. The melting point of this product is 133-140°C.

Analysis. Calculated for C25H26N4O(N2O)of 0.2: %74,67; %N, 6,62; %N, 13,93. Found: %74,65; %N, 6,60; %N, 14,00.

1H NMR(300 MHz, DMSO-d6) δ 8,08 (doublet, J=7.8 Hz, 1H), to 7.61 (doublet, J=7,3 Hz, 1H), 7,41 (triplet, J=7,3 Hz,1H), 7,29 was 7.36 (multiplet, 3H), 7,17-7,24 (multiplet, 3H), 6,45 (singlet, 2H), 4,78 (triplet, J=4,9 Hz, 2H), 4,34 (singlet, 2H), 4,01 (triplet, J=4,9 Hz, 2H), 2.95 and (triplet, J=8,3 Hz, 2H), is 1.81 (quintet, J=7,3, 8,3 Hz, 2H), of 1.44 (sextet, J=7,3, to 7.3, and 7.8 Hz, 2H), 0,93 (triplet, J=7,3 Hz, 3H)

MS(Cl) for C25H26N4O m/z 399 (MN+), 283, 267.

Example 124

2-Butyl-1-[2-(3-phenylpropoxy)ethyl])-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 12, part b, carry out the hydrogenation of 2-butyl-1-{2-[(3-phenylprop-2-inyl)oxy]ethyl}-1H-imidazo[4,5-C]quinoline (2.4 g, 6,26 mmole) 2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline (1,67 g), a white solid product.

MS(Cl) for C25H29N3About m/z 388 (MH+), 279.

Part b

Using the primary method used in example 1, part b, 1.68 g (4,34 mmole) of 2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline oxidizes to 1.75 g of 2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide, representing a glassy solid product.

MS(Cl) for C25H29N3O2m/z 404 (MN+), 388.

The part With

Using the primary method used in example 115, part With, spend amination of 1.75 g (4,34 mmole) of 2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide. Formed as a result of this reaction, the solid is yuvati product is recrystallized from acetonitrile, resulting 0,572 g of 2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine in the form of yellowish-brown crystalline solid. The melting point of this product is 80,8-81,3°C.

Analysis. Calculated for C25H30N4O(H2O)for 0.3: %C 73,61; %N, 7,56; %N, 13,73. Found: %73,3; %N, 7,65; %N, 13,67.

1H NMR(300 MHz, DMSO-d6) δ 8,07 (doublet, J=8,3 Hz, 1H), 7.62mm (doublet, J=8,3 Hz, 1H), 7,41 (triplet, J=7,3 Hz, 1H), 7,21 (triplet, J=7,3 Hz, 1H), 7,05-7,14 (multiplet, 3H), 6.89 in (doublet, J=7,3 Hz, 2H), 6,45 (singlet, 2H), 4,74 (triplet, J=4.4 Hz, 2H), 3,80 (triplet, J=4,9 Hz, 2H), 3,24 (triplet, J=5,9 Hz, 2H), 2,98 (triplet, J=7.8 Hz, 2H), 2,39 (triplet, J=7.8 Hz, 2H), of 1.84 (quintet, J=7,3, 8,3 Hz, 2H), of 1.62 (quintet, J=7,8 and 5.9 Hz, 2H), to 1.48 (sextet, J=7,3, to 7.3, and 7.8 Hz, 2H), 0.95 (triplet, J=7,3 Hz, 3H)

MS(Cl) for C25H30N4O m/z 403 (MN+), 213.

Example 125

1-[2-(Benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 1, part b, carry out the oxidation 0,324 g (0,897 mmole) 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline, resulting in a gain 0,338 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide as a brown oil.

Part b

Using the primary method used in example 115, part With, spend amination 0,339 g (0,897 IMO is I) 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide. Formed as a result of this reaction, the solid yellowish-brown product is recrystallized from acetonitrile, resulting in Poluchenie,187 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine as a white powder. The melting point of this product is 144.5-146,0°C.

Analysis. Calculated for C22H24N4O2: %70,19; %N, TO 6.43; %N, 14,88. Found: %69,96; %N, 6,29; %N, 15,09.

1H NMR(300 MHz, DMSO-d6) δ 8,08 (doublet, J=7.8 Hz, 1H), to 7.61 (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=6,8 Hz, 1H), 7,19-7,24 (multiplet, 4H), 7,11-7,14 (multiplet, 2H), 6,6 (singlet, 2H), 4,87 (triplet, J=5.4 Hz, 2H), 4,79 (singlet, 2H), of 4.44 (singlet, 2H), 3,90 (triplet, J=5.4 Hz, 2H), 3,90 (quintet, J=6,8, 6,8 Hz, 2H), 1,13 (triplet, J=6,8 Hz, 3H)

MS(Cl) for C22H24N4O2m/z 377 (MH+), 331, 241.

Example 126

1-[2-(Benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the primary method used in example 1, part b, carry out the oxidation of 2.3 g (6,39 mmole) 1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline, resulting in a gain of 2.4 g of 1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-5N-oxide as a brown oil.

MS(Cl) for C23H25N3O2m/z 376 (MH+), 360, 270.

Part b

Using the primary method used in example 1, part C, 2.4 g (6,39 mmole) 1-[2-(benzylic and)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-5N-oxide process trichlorotriazine (1.45 g, 7,678 mmole), resulting in the formation of 3.3 g of brown oily N-{1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-4-yl}-2,2,2-trichloroacetamide.

The part With

3.3 grams (6,39 mmole) of N-{1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-quinoline-4-yl}-2,2,2-trichloroacetamide subjected to hydrolysis under the action of sodium methylate (5 ml, 25%solution in methanol) according to the method used in example 1, part D. the Resulting reddish solid is subjected to chromatographic purification on silica gel (eluent is a mixture 98/2 dichloromethane/methanol), and then recrystallized from methanol and dried in vacuum at 60°C for 18 hours. The result 0,174 g of a white solid of 1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 133-135°C.

Analysis. Calculated for C23H26N4ABOUT: %73,77; %N, 7,00; %N, 14,96. Found: %73,51 ;%N, 7,06; %N, 14,92.

1H NMR(300 MHz, DMSO-d6) δ 8,03 (doublet, J=7,3 Hz, 1H), 7,60 (doublet, J=8,3 Hz, 1H), 7,39 (triplet, J=6,8 Hz, 1H), 7,17-7,24 (multiplet, 4H), 7,10-7,12 (multiplet, 2H), 6,45 (singlet, 2H), 4,76 (triplet, J=5.4 Hz, 2H), to 4.41 (singlet, 2H), 3,89 (triplet, J=4,9 Hz, 2H), 2,94 (triplet, J=8,3 Hz, 2H), 1.77 in (quintet, J=7,8, and 7.8 Hz, 2H), of 1.40 (sextet, J=7,8, 7,3, 6,8 Hz, 2H), 0,91 (triplet, J=7,3 Hz, 3H)

MS(Cl) for C23H26N4O m/z 375 (MH+), 242,183.

Example 127

1-[2-(Benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]hee the Olin-4-amine

Part a

Using the primary method used in example 1, part b, carry out the oxidation of 6 g (18.9 mmole) 1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]quinoline, resulting in a gain of 6.3 g of 1-[2-(benzyloxy)ethyl}-2-methyl-1H-imidazo[4,5-C]quinoline-5N-oxide as a brown solid.

Part b

Using the primary method used in example 1, part C, 6.3 g (18.9 mmole) 1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]quinoline-5N-oxide process trichlorotriazine (4,95 g, 26,27 mmole), resulting in a 10.4 g of a brown solid, N-{1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]quinoline-4-yl}-2,2,2-trichloroacetamide.

The part With

10,46 g (21,89 mmole) of N-{1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]quinoline-4-yl}-2,2,2-trichloroacetamide subjected to hydrolysis under the action of sodium methylate (20 ml, 25%solution in methanol) according to the method used in example 1, part D. the Resulting brown solid is subjected to chromatographic purification on silica gel (eluent is a mixture 98/2 dichloromethane/methanol) and dried in vacuum at 60°C for 18. The result 1,036 g of a white solid of 1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 159-160°C.

Analysis. Calculated for C20H20N4O: %72,27; %N, 6,06; %N, 16,85. ideno: %72,17; %N, 5,96; %N, THE VALUE OF 16,81.

1H NMR(300 MHz, DMSO-d6) δ 8,04 (doublet, J=7,3 Hz, 1H), to 7.59 (doublet, J=8,3 Hz, 1H), 7,39 (triplet, J=8,3 Hz, 1H), 7,15-7,27 (multiplet, 4H), 7,08-7,13 (multiplet, 2H), of 6.49 (singlet, 2H), 4.75 in (triplet, J=5.4 Hz, 2H), 4,43 (singlet, 2H), 3,90 (triplet, J=5.4 Hz, 2H), 2,61 (singlet, 3H)

MS(Cl) for C20H20N4O m/z 333 (MN+), 243, 199.

Example 128

1-[2-(Benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinoline-4-amine

Part a

Using the primary method used in example 1, part b, carry out the oxidation of 2.4 g (5.8 mmole) of 1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-C]quinoline, resulting in a gain of 2.5 g of 1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-C]quinoline-5N-oxide as a brown oil.

Part b

Using the primary method used in example 115, part With, spend amination of 2.50 g (5,80 mmole) 1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-C]quinoline-5N-oxide. The resulting oil is subjected to khromatograficheskoi purification on silica gel (eluent is a mixture 98/2 dichloromethane/methanol) and recrystallized from acetonitrile. The result is 0.75 g of solid white 1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-C]quinoline-4-amine, melting point which is 110-111°C.

Analysis. Calculated for C27H34N4O: %75,31; %N, OF 7.96; %N, 13,01. Found: %75,20; %N, 7,88; %N, 13,00.

1H NMR(300 MHz, DMSO-d 6) δ 8,03 (doublet, J=7.8 Hz, 1H), 7,60 (doublet, J=8,3 Hz, 1H), 7,40 (triplet, J=7,3 Hz, 1H), 7,17-7,26 (multiplet, 4H), 7,10-7,13 (multiplet, 2H), 6,45 (singlet, 2H), 4,76 (triplet, J=4,9 Hz, 2H), to 4.41 (singlet, 2H), 3,88 (triplet, J=4,9 Hz, 2H), 2,93 (triplet, J=7.8 Hz, 2H), 1,79 (Quintett, J=7,3, 7,3 Hz, 2H), 1,20-1,38 (multiplet, 10H), 0,85 (triplet, J=6.3 Hz, 3H)

MS(Cl) for C27H34N4O m/z 431 (MH+), 291, 214.

Example 129

2-(2-Methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-quinoline-4-amine

Part a

17.6 ml (0,13 mol) of 2-phenoxyethylamine dropwise in a nitrogen atmosphere add to cooled in an ice bath to a solution of 21.5 g (0.1 mole) 4-chloro-3-nitroquinoline and 21.5 ml of 0.16 mol) of triethylamine in 500 ml of dichloromethane. The reaction mixture was kept overnight at ambient temperature, then add it to the water and separating the aqueous phase from the organic phase. The organic phase is dried over magnesium sulfate, filtered and the solvent is distilled off in vacuum. To the residue add hexane, and the solution is cooled in the refrigerator. The formed precipitate is removed by vacuum filtration and the result of 19.1 g of 3-nitro-N-(2-phenoxyethyl)quinoline-4-amine in the form of a yellow solid substance.

Part b

In the apparatus for carrying out the hydrogenation load of 6.0 g (19 mmol) of 3-nitro-N-(2-phenoxyethyl)quinoline-4-amine, 1.5 g of activated charcoal coated with not what about the platinum (5%) and 300 ml of ethyl acetate. The mixture is shaken overnight under hydrogen pressure of 40 pounds/inch2(2.8 kg/cm2), after which the mixture was filtered and the remaining on the filter, the catalyst was washed with ethyl acetate. The filtrate is dried over magnesium sulfate, filtered and evaporated to dryness in a vacuum. To the residue add hexane, and the resulting precipitate was separated by vacuum filtration. The result of 4.9 g of a pale yellow solid N4-(2-phenoxyethyl)quinoline-3,4-diamine.

The part With

It chilled in an ice bath to a solution of 2.0 g (7.2 mmole) of N4-(2-phenoxyethyl)quinoline-3,4-diamine in 100 ml of dichloromethane is added dropwise within 30 minutes add 0,86 ml (7,9 mmole) of the acid chloride of 3-methoxypropanol acid. After a few hours, the formation of sludge. The solvent is evaporated in vacuo almost to dryness and add 100 ml of hexane. After vacuum filtration obtain 2.9 g of hydrochloric acid salt of 3-methoxy-N-{4-[(2-phenoxyethyl)amino]quinoline-3-yl}propanamide.

Part D

Derived in part From the product (2.9 g) and 200 ml of 7.5%aqueous methanolic solution of ammonia load in the autoclave. The autoclave is closed and heated at 160°C for 6 hours. After that the reaction mixture is cooled to ambient temperature and concentrated in vacuo. The residue is partitioned between 150 ml of dichloromethane and 150 ml of water. Separate the aqueous and organic phase and the aqueous phase EC is tracerout 100 ml of dichloromethane. The organic fractions are combined together, dried over magnesium sulfate and filtered. The solvent is removed in vacuo and to the residue add hexane to yield a white precipitate. After vacuum filtration obtain 1.8 g of white solid 2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline.

Part E.

To a solution of 1.8 g (5.2 mmole) of 2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline in 100 ml of chloroform three portions over 20 minutes, add 1.5 g (8.7 mmole) 60%3-chloroperoxybenzoic acid. The reaction mixture was kept overnight at ambient temperature, then washed first with saturated aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate and concentrated in vacuo almost to dryness. To the residue add hexane and after vacuum filtration of the resulting precipitate obtain 1.6 g of 2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide as a pale yellow powder.

Part F

0.8 ml (6.6 mmole) trichloroacetimidate in nitrogen atmosphere are added dropwise to a solution of 1.6 g (4.4 mmole) of 2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide in 100 ml of dichloromethane, and the reaction mixture is incubated at ambient temperature for 2 hours. Then to the mixture is added 5 drops 7%methanolic solution of ammonium hydroxide and in the support mixture at ambient temperature for 2.5 days. After this time, add 10%sodium hydroxide solution and share the water and organic phases. The organic phase is concentrated and purified by way of flash chromatography on silica gel, using as eluent a mixture of 9:1 dichloromethane: methanol. The fractions containing the product are combined together, concentrated in vacuo, dissolved in boiling toluene and treated with activated carbon. The mixture is filtered to remove the activated charcoal and the filtrate is cooled. The formed precipitate is filtered off and after drying in a vacuum oven at 80°With gain of 0.68 g of 2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine as a yellowish brown powder. The melting point of this product is 171,0-174,0°C.

1H NMR(300 MHz, DMSO-d6) δ 8,19 (doublet, J=8,1 Hz, 1H), to 7.64 (doublet, J=8,3 Hz, 1H), 7,44 (triplet, J=7.5 Hz, 1H), 7,29-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,4 Hz, 1H), 6,82 (doublet, J=8,2 Hz, 2H), 6,58 (singlet, 2H), 5,01 (triplet, J=5.0 Hz, 2H), 4,43 (triplet, J=5,0 Hz, 2H), a 3.87 (triplet, J=6,9 Hz, 2H), 3,34 (singlet, 3H), 3,30 (triplet, J=6,9 Hz, 2H);

MS(Cl) m/e 363,1820 (363,1821 calculated for C21H23N4O2M+N);

Analysis. Calculated for C21H22N4O2: %69,59; %N, 6,12; %N, 15,46. Found: %69,32; %N, 6,17; %N, 15,48.

Example 130

2-Isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

A mixture of 1.5 g (5.4 mmole) of N4-(2-phenoxyethyl)quinoline-3,4-diamine and 0.8 ml (6.4 mmole) of the acid chloride isovalerianic acid is treated in the same manner as described in example 129, part-that is, Formed as a result of this treatment, the product is 2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-5N-oxide (1.6 g, 4.5 mmole) was dissolved in 200 ml of dichloromethane and to the solution add 50 ml of ammonium hydroxide. The reaction mixture was cooled in an ice bath and slowly over 20 min add to it 0,85 g (4.5 mmole) of the acid chloride p-toluensulfonate acid. The cooling bath removed and the mixture is incubated at ambient temperature over night. Separate the aqueous and organic phases. The organic phase is washed successively with 1%aqueous sodium carbonate solution (3 times), water and brine, then dried over sodium sulfate and evaporated in vacuum to dryness. Add hexane. The precipitate is collected and recrystallized from acetonitrile. The result is 0.96 g of 2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine in the form of a yellowish-brown powder, melting point which is 176,6-of 177.8°C.

1H NMR(300 MHz, DMSO-d6) δ 8,16 (doublet, J=8,2 Hz, 1H), 7,63 (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=7,6 Hz, 1H), 7,28-7.20 (multiplet, 3H), 6.89 in (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=8.6 Hz, 2H), of 6.49 (singlet, 2H), 4,98 (triple the t, J=4,8 Hz, 2H), 4,42 (triplet, J=4,8 Hz, 2H), 2,89 (doublet, J=7.2 Hz, 2H), 2.40 a-2,22 (multiplet, 1H), 1,02 (doublet, J=6,6 Hz, 6N);

13With NMR(75 MHz, DMSO-d6) 158,6, 153,9, 152,4, 145,5, 132,9, 130,1, 127,1, 126,9, 121,5, 120,8, 115,3, 114,7, 66,6, 44,4, 35,3, 27,1, 22,4;

MS(Cl) m/e 361,2017 (361,2028 calculated for C22H25N4O M+N);

Analysis. Calculated for C22H24N4O: %73,31; %N, OF 6.71; %N, 15,54. Found: %73,33; %N, 6,56; %N, 15,79.

Example 131

2-Isopropyl-1-(2-phenoxyethyl)- 1H-imidazo[4,5-C]quinoline-4-amine

A mixture of 2.0 g (7.2 mmole) of N4-(2-phenoxyethyl)quinoline-3,4-diamine and 0.9 ml (8.6 mmole) of the acid chloride somaclonal acid is treated in the same manner as described in example 130. Recrystallization of the resulting product from acetonitrile gives 0,82 g 2-isopropyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine as a yellowish brown powder. The melting point of this product is 229-231°C.

1H NMR(300 MHz, DMSO-d6) δ 8,17 (doublet, J=7.5 Hz, 1H), 7,65-7,62 (double doublet, J=8,3, 1.1 Hz, 1H), 7,46-7,40 (double triplet, J=8,2, 1.1 Hz, 1H), 7,29-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=7.8 Hz, 2H), 6,46 (singlet, 2H), 5,01 (triplet, J=4,9 Hz, 2H), 4,42 (triplet, J=4,9 Hz, 2H), 3,54 (septet, J=6.8 Hz, 1H), 1,41 (doublet, J=6,8 Hz, 6N);

13With NMR(75 MHz, DMSO-d6) 159,3, 158,5, 152,3, 145,4, 132,6, 130,1, 126,84, 126,78, 121,5, 120,7, 115,3, 114,6, 66,5, 44,1, 25,2, 21,8;

MS(Cl) m/e 347,1872 (347,1872 calculated for C21 H23N4O M+H);

Analysis. Calculated for C21H22N4O: %72,81; %N, 6,40; %N, 16,17. Found: %72,48; %N, 6,59; %N, 16,50.

Example 132

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

A mixture of 2.0 g (7.2 mmole) of N4-(2-phenoxyethyl)quinoline-3,4-diamine, 150 ml of xylene and 2.5 ml (14.3 mmole) of triethylorthoformate in nitrogen atmosphere refluxed for 4 days. After the heat increase and distilled to approximately 35 ml of xylene. The reaction mixture is slowly cooled to ambient temperature, and the resulting precipitate. After vacuum filtration of the solid product is obtained 2.4 g of yellowish-brown crystalline solid 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline.

2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline treated in the same manner as in example 129, parts E and F. Recrystallization of the final product from acetonitrile gives of 0.93 g of 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine in the form of white needle crystals. The melting temperature of the target product is 168,3-169, 5mm°C.

1H NMR(300 MHz, DMSO-d6) δ 8,16 (doublet, J=8,1 Hz, 1H), 7,63 (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=7,6 Hz, 1H), 7,28-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,4 Hz, 1H), 6,82 (doublet, J=8.5 Hz, 2H), 6,47 (singlet, 2H), equal to 4.97 (triplet, J=4,8 Hz, 2H), 4,43 (triplet, J=4,8 Hz, H), 3,00 (triplet, J=7.7 Hz, 2H), 1,86 (multiplet, 2H), 1,47 (multiplet, 2H), 0,96 (triplet, J=7,3 Hz, 3H);

13With NMR(75 MHz, DMSO-d6) 158,5, 154,6, 152,3, 145,6, 132,9, 130,1, 126,8, 121,5, 120,7, 115,2, 114,6, 66,7, 44,4, 29,3, 26,2, 21,9, 13,6;

MS(Cl) m/e 361,2032 (361,2028 calculated for C22H25N4O M+N);

Analysis. Calculated for C22H24N4O: %73,31; %N, OF 6.71; %N, 15,54. Found: %73,15;%H,6,69;%N,15,57.

Example 133

1-(2-Phenoxyethyl)-2-(phenoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 129, part, conduct the reaction between phenoxyacetamide (1.2 ml, 8.6 mmole) and N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmole). Formed at this stage, the product is treated in the same manner as in example 129, stage D-F. Recrystallization of the final product from acetonitrile gives 0.65 g of a yellowish-brown powder, which represents a 1-(2-phenoxyethyl)-2-(phenoxymethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 168,5-170,0°C.

1H NMR(300 MHz, DMSO-d6) δ 8,25 (doublet, J=7.9 Hz, 1H), to 7.64 (double doublet, J=8,3, 1.0 Hz, 1H), 7,47 (multiplet, 1H), 7,38-7,14 (multiplet, 7H), 7,01 (triplet, J=7,3 Hz, 1H), 6.89 in (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=7.8 Hz, 2H), 6,69 (singlet, 2H), of 5.53 (singlet, 2H), from 5.29 (triplet, J=5.0 Hz, 2H), 4,48 (triplet, J=5.0 Hz, 2H);

13With NMR(75 MHz, DMSO-d6) 158,5, 152,7, 149,2, 146,1, 134,1, 1302, 130,1, 127,6, 127,0, 126,9, 122,0, 121,6, 121,5, 121,4, 115,3, 114,7, 66,6, 62,7, 45,0;

MS(Cl)m/e 411,1813 (411,1821 calculated for C25H23N4O2M+N);

Analysis. Calculated for C25H22N4O2: %73,15; %N, 5,40; %N, 13,65. Found: %73,36; %N, 5,30; %N, 13,66.

Example 134

2-(4-Methoxybenzyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 129, part, conduct the reaction between 4-methoxyphenylacetylene (1.2 ml, of 7.9 mmole) and N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmole). Formed at this stage, the product is treated in the same manner as in example 129, stage D-F. Recrystallization of the final product from acetonitrile gives 1.1 g of a yellowish brown solid, which represents a 2-(4-methoxybenzyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 201,0-203,6°C.

1H NMR(300 MHz, DMSO-d6) δ 8,15 (doublet, J=8,1 Hz, 1H), 7,63 (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=7,6 Hz, 1H), 7,26-7,18 (multiplet, 5H), 6,93-6,87 (multiplet, 3H), 6,74 (doublet, J=8,2 Hz, 2H), 6,58 (singlet, 2H), 4,89 (triplet, J=5,1 Hz, 2H), 4,40 (singlet, 2H), 4,24 (triplet, J=5,1 Hz, 2H), 3,70 (singlet, 3H);

MS(Cl) m/e 425,1948 (425,1978 calculated for C26H25N4O2M+N);

Analysis. Calculated for C26H24N4O2: %73,57; %N, 5,70; %N, 13,20. Found: %7,25; %N, 5,93; %N, 13,06.

Example 135

2-Cyclopentyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 130, conduct the reaction between the N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmole) and cyclopentanecarbonitrile (1.1 ml, 8.6 mmole). Recrystallization of the final product from acetonitrile gives 1.4 g of a yellowish brown solid, which represents a 2-cyclopentyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 216,0-217,9°C.

1H NMR(300 MHz, DMSO-d6) δ 8,17 (doublet, J=8,1 Hz, 1H), 7,63 (doublet, J=8,2 Hz, 1H), 7,43 (triplet, J=7,6 Hz, 1H), 7,28-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=8.5 Hz, 2H), 6,46 (singlet, 2H), 5,02 (triplet, J=4,9 Hz, 2H), 4,42 (triplet, J=4,9 Hz, 2H), 3,60 (quintet, J=8,2 Hz, 1H), 2,18-1,67 (multiplet, 8H);

13With NMR(75 MHz, DMSO-d6) 158,5, 158,3, 152,9, 144,6, 133,0, 130,1, 126,8, 121,5, 120,8, 115,3, 114,7, 66,5, 44,2, 36,1, 32,3, 25,3;

MS(Cl) m/e 373,2030 (373,2028 calculated for C23H25N4O M+N);

Analysis. Calculated for C23H24N4O: %74,17; %N, OF 6.49; %N, 15,04. Found: %74,18; %N, 6,59; %N, 15,08.

Example 136

2-[(2-Methoxyethoxy)methyl]-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 130, conduct the reaction between the N4-(2-phenoxyethyl)hin the Lin-3,4-diamine (2.0 g, 7.2 mmole) and 2-(2-methoxyethoxy)-acetylchloride (1.3 g, 8.6 mmole). Recrystallization of the final product from methanol gives 1.6 g of 2-[(2-methoxyethoxy)methyl]-1-(2-phenoxyethyl)-1H-imidazo[4,5-finalen-4-amine in the form of white needle crystals. The melting point of this product is in the range 170,0-which is 171,5°C.

1H NMR(300 MHz, CDCl3) δ 8,06 (double doublet, J=8,3, 1.0 Hz, 1H), 7,82 (double doublet, J=8,4, 1.0 Hz, 1H), 7,55-7,50 (multiplet, 1H), 7,35-7,29 (multiplet, 1H), 7,26-7,18 (multiplet, 2H), 6,92 (triplet, J=7,4 Hz, 1H), 6,79 (double doublet, J=8,7, 0.9 Hz, 2H), 5,57 (singlet, 2H), 5,07 (triplet, J=5,9 Hz, 2H), 5,00 (singlet, 2H), 4,47 (triplet, J=5,9 Hz, 2H), 3,71 (multiplet, 2H), 3,55 (multiplet, 2H), 3,31 (singlet, 3H);

13With NMR(75 MHz, DMSO-d6) 158,9, 152,3, 150,3, 146,2, 135,2, 130,3, 128,3, 128,2, 127,6, 123,1, 122,2, 120,6, 116,1, 115,1, 72,1, 70,2, 66,6, 66,3, 59,3, 45,6;

MS(Cl) m/e 393,1912 (393,1927 calculated for C22H25N4O3M+N);

Analysis. Calculated for C22H24N4O3: %67,33; %N, 6,16; %N, 14,27. Found: %67,62; %N, 6,24; %N, 14,37.

Example 137

2-(Cyclopropylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 130, conduct the reaction between the N4-(2-phenoxyethyl)quinoline-3,4-diamine (1.7 g, 6.1 mmole) and cyclopropylacetylene (0,86 ml, 7.3 mmole). Recrystallization of the final product from methanol gives 0,86 g of the white solid in the society, represents 2-(cyclopropylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 191,7-192,6°C.

1H NMR(300 MHz, AMCO-d6) δ 8,17 (doublet, J=7.5 Hz, 1H), 7,63 (double doublet, J=8,3, 1.1 Hz, 1H), 7,46-7,41 (multiplet, 1H), 7,28-7,19 (multiplet, 3H), 6.89 in (triplet, J=7,3 Hz, 1H), 6,79 (doublet, J=7.8 Hz, 2H), of 6.49 (singlet, 2H), 4,98 (triplet, J=5.0 Hz, 2H), 4,42 (triplet, J=5,0 Hz, 2H), 2,99 (doublet, J=6,7 Hz, 2H), 1,40-1,26 (multiplet, 1H), 0,55 (multiplet, 2H), 0,32 (multiplet, 2H);

13With NMR(75 MHz, DMSO-d6) 158,6, 154,1, 152,4, 145,5, 133,1, 130,1, 127,0, 126,9, 121,5, 120,8, 115,2, 114,7, 72,1, 66,6, 44,5, 31,1,10 9,0, 4,6;

Analysis. Calculated for C22H22N4O. 0,1N2O: %73,35; %N, 6,21; %N, 15,55. Found: %73,23; %N, Of 6.31; %N, 15,57.

Example 138

2-(2-Cyclopentylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 129, part, conduct the reaction between cyclopentylpropionate (1.3 ml, 8.6 mmole) and N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmole). Obtained at the last stage of the reaction product is treated in the same manner as described in example 129, part D-F. Recrystallization of the final product from acetonitrile gives of 0.44 g of the target substance - 2-(cyclopentylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine as a white powder. The melting point of the product p is BHA 165,0° C.

1H NMR(300 MHz, DMSO-d6) δ 8,17 (doublet, J=8.0 Hz, 1H), to 7.64 (double doublet, J=8,3, 0.8 Hz, 1H), 7,44 (triplet, J=7,3 Hz, 2H), 7,29-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=7.9 Hz, 2H), 6,60 (singlet, 2H), equal to 4.97 (triplet, J=4,6 Hz, 2H), of 4.44 (triplet, J=4,6 Hz, 2H), 3.00 and (triplet, J=7,6 Hz, 2H), 1.91 a-1,77 (multiplet, 5H), 1,64 is 1.48 (multiplet, 4H), 1,20-1,14 (multiplet, 2H);

13With NMR(75 MHz, DMSO-d6) 158,2, 155,0, 151,5, 144,7, 133,6, 129,9, 127,5, 127,4, 127,0, 122,6, 121,9, 119,5, 115,5, 114,5, 66,0, 45,7, 39,8, 32,3, 26,4, 24,9;

MS(Cl)m/e 401,2336 (401,2341 calculated for C25H29N4O, M+H);

Analysis. Calculated for C25H18N4O. 0.1H2O: %C 74,97; %N, 7,05; %N, 13,99. Found: %74,67; %N, 7,11; %N, 13,97.

Example 139

1-(2-Phenoxyethyl)-2-tetrahydrofuran-3-yl-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 130, conduct the reaction between the N4-(2-phenoxyethyl)quinoline-3,4-diamine (1.6 g, 5.7 mmole) and the acid chloride tetrahydrofuran-3-carboxylic acid (0,98 ml, 7.3 mmole). Recrystallization of the final product from acetonitrile gives 0.3 g of a yellowish brown solid, which represents a 1-(2-phenoxyethyl)-2-tetrahydrofuran-3-yl-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is 235,9-36,3°C.

1H NMR(300 MHz, AMCO-d6) δ 8,18 (doublet, J=7.8 Hz, 1H), 7,63 (double doublet, J=8,3, 1.0 Hz, 1H), 7,44 (double triplet, J=7,6, ,0 Hz, 1H), 7,29-7,20 (multiplet, 3H), 6.90 to (triplet, J=7,3 Hz, 1H), for 6.81 (doublet, J=798 Hz, 2H), of 6.49 (singlet, 2H), of 5.05 (triplet, J=4,9 Hz, 2H), 4,42 (triplet, J=4,9 Hz, 2H), 4,24 (multiplet, 1H), 4.04 the-3,98 (multiplet, 3H), 3,92-a 3.87 (multiplet, 1H), 2,50-2,30 (multiplet, 2H);

13With NMR(75 MHz, DMSO-d6) 158,6, 155,2, 152,4, 145,5, 133,2, 130,1, 127,0, 126,9, 121,6, 120,3, 115,2, 114,7, 72,1, 68,0, 66,5, 44,4, 36,0, 32,4;

MS(Cl) m/e 375,1808 (375,1821 calculated for C22H23N4O2, M+N);

Analysis. Calculated for C22H22N4O. 0,25H2O: %69,73; %N, 5,98; %N, 14,78. Found: %769290 %N, 5,91; %N, The 14.90.

Example 140

1-(2-Phenoxyethyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine

Using the methodology described in example 129, part, conduct the reaction between the acid chloride of benzoic acid (1.0 ml, 8.5 mmole) and N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmole). Formed at this stage, the product is treated in the same manner as in example 129, stage D-F. Recrystallization of the final product from methanol gives 0.74 g of a yellowish brown solid, which represents a 1-(2-phenoxyethyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this product is in the range 182,5-184,6°C.

1H NMR(300 MHz, DMSO-d6) δ 8,21 (doublet, J=7.9 Hz, 1H), 7,83-7,79 (multiplet, 2H), 7.68 per-7,58 (multiplet, 4H), of 7.48 (triplet, J=7,3 Hz. 1H), 7,29 (triplet, J=7,3 Hz, 1H), 7,16 (multiplet, 2H) 6,85 (triplet, J=7,3 Hz, 1H), 6,68 (multiplet, 4H), 5,02 (triplet, J=5,1 Hz, 2H), 4,33 (triplet, J=5,1 Hz. 2H);

13With NMR(75 MHz, DMSO-d6) 158,2, 153,6, 152,9, 146,0, 133,6, 131,1, 130,8, 130,3, 130,1, 129,3, 127,9, 127,5, 127,1, 121,9, 121,6, 121,2, 115,4, 114,7, 66,1, 45.6;

MS(Cl) m/e 381,1703 (381,1715 calculated for C24H21N4O, M+H);

Analysis. Calculated for C24H20N4O. 0,25H2O: %C 74,88; %H, LOWER THAN THE 5.37; %N, 14,55. Found: %74,42; %N, 5,10; %N, 14, 48mm.

Example 141

4-{[(2-(4-Amino-1H-imidazo[4,5-C]quinoline-1-yl)butoxy]methyl}benzonitrile

Part a

To a stirred mixture of 3.0 g (15.3 mmole) α-bromo-p-toluenethiol, 40 ml of 50%aqueous sodium hydroxide solution, 40 ml of dichloromethane and 0.02 g (of 0.11 mmole) of benzyltrimethylammonium add 3.0 g (12.4 mmole) of 2-(1H-imidazo[4,5-C]quinoline-1-yl)-1-butanol. The reaction mixture was incubated for 72 hours and then diluted by adding 100 ml of water and dichloromethane. Separate the aqueous and organic phases. The aqueous phase is extracted with additional quantity (100 ml) of dichloromethane. The organic fractions are combined together, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to purification using flash chromatography (silica gel, 9/1 dichloromethane/methanol, Rf of 0.48). As a result of 2.66 g of 4-{[(2-(1H-imidazo[4,5-C]quinoline-1-yl)butoxy]methyl}benzonitrile.

Part b

To a solution of 2.6 g (7.3 mmole) 4-{[(2-(1H-they are the azo[4,5-C]quinoline-1-yl)butoxy]-methyl}benzonitrile in 70 ml of chloroform is slowly added 2.2 g (7.5 mmole) of 60%3-chloroperoxybenzoic acid. The reaction mixture was incubated for 2 hours and then washed successively first with a saturated solution of sodium bicarbonate (200 ml) and twice with water (100 ml). The washed product is dried over magnesium sulfate, filtered and concentrated to obtain 2.7 g of the corresponding 5N-oxide.

The part With

1,43 g (7.5 mmole) of the acid chloride p-toluensulfonate acid is added slowly to a cooled to 0°With a mixture containing the reaction product obtained in part b (2.7 g, 7.3 mmole), 10 ml of concentrated ammonium hydroxide solution and 20 ml of dichloromethane. Reaction monitoring using the method of thin layer chromatography (9:1 dichloromethane:methanol) shows that the reaction is completed in several minutes. After that the reaction mixture is heated to ambient temperature and separate the aqueous and organic phases. The organic phase is successively washed with aqueous sodium carbonate solution (three times), water and brine, dried over sodium sulfate and concentrated in vacuo. Purification of the resulting brown oil by way of flash chromatography (silica gel, 92/8 dichloromethane/methanol) followed by repeated recrystallization from a mixture of ethyl acetate/hexane gives 0.45 g of a yellowish-brown powder 4-[[(2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butoxy]methyl}benzonitrile. The melting point of the pure product composition is employed, 160,0-161,0° C.

1H NMR(300 MHz, DMSO-d6) δ to 8.41 (singlet, 1H), 8,20 (doublet, J=7,3 Hz, 1H), to 7.67 (multiplet, 3H), 7,44 (triplet, J=7,3 Hz, 1H), 7,31-7,21 (multiplet, 3H), 6,72 (singlet, 2H), 5,26 (broad singlet, 1H), 4,54 (singlet, 2H), was 4.02-3,91 (multiplet, 2H), 2,07 (multiplet, 2H), 0,87 (triplet, J=7,3 Hz, 3H);

13With NMR(125 MHz, DMSO-d6) 152,2, 145,2, 143,8, 140,1, 132,4, 132,0, 127,5, 126,6, 126,4, 121,0, 120,5, 118,7, 115,0, 110,0;

MS(El) m/e 371,1754 (371,1746 calculated for C22H21N5O);

Analysis. Calculated for C22H21N5O: %71,14; %N, 5,70; %N 18,85. Found: %70,78; %N, 5,65; %N, 18,51.

Example 142

4-({[(2R)-2-(4-Amino-1H-imidazo[4,5-quinoline-1-yl)butyl]oxy}methyl)benzonitrile

In accordance with the principal methodology used in parts a and b of example 141, carry out the conversion of (2R)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol (1,36 g, 5.3 mmole) 1.60 g of the corresponding 5N-oxide product.

To a solution of 1.60 g of the obtained 5N-oxide in 25 ml of dichloromethane are added dropwise of 0.77 ml (6.5 mmole) trichloroacetimidate. The reaction mixture was kept overnight and then concentrated in vacuo. The resulting red oil was dissolved in 25 ml of methanol and to the solution was added to 4.0 ml of a 21%solution of sodium methylate in methanol. The mixture was incubated for 2.5 days. The solvent is removed in vacuo and the remaining crude product is subjected to chromatographic clear the e on silica gel, using 92/8 mixture of dichloromethane/methanol as eluent, and then recrystallized from methyl acetate. The result is a white solid product, a 4-{[((2R)-2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]oxy}methyl)-benzonitrile. According to liquid chromatography (column: CHIRALCEL® OD-RH; eluent: 90/10/0,2 pentane/methanol/triethylamine; flow rate 2 ml/min, retention time Rt 7,8 minutes) the final product contains more than 99% of the enantiomer.

1H NMR(500 MHz, DMSO-d6) δ 8,39 (singlet, 1H), 8,20 (doublet, J=7.8 Hz, 1H), 7,69 (doublet, J=8,1 Hz, 2H), 7,63 (double doublet, J=8,3, 1.1 Hz, 1H), 7,45-7,42 (multiplet, 1H), 7,31 (doublet, J=8,1 Hz, 2H), 7.23 percent (multiplet, 1H), 6,58 (singlet, 2H), 5,27 (broad singlet, 1H), 4,57 (singlet, 2H)that is 4.03 (double doublet, J=10,3, 6,8 Hz, 1H), 3,93 (double doublet, J=10,3, 3,9 Hz, 1H), 2,09 (multiplet, 2H), 0,89 (triplet, J=7,3 Hz, 3H);

Analysis. Calculated for C22H21N5O: %71,14; %N, 5,70; %N 18,85. Found: %71,00; %N, 5,66; %N, 18,64.

Example 143

4-({[(2S)-2-(4-Amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]oxy}methyl)benzonitrile

The conversion of (2S)-2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol (1.3 g) until the desired product is carried out in accordance with the basic method used in example 142. Recrystallization of the final product from a mixture of ethyl acetate/hexane gives 0.2 g solid white 4-{[((2S)-2-(4-amino-1H-imidazo[4,5-C]hin the Lin-1-yl)butyl]oxy}methyl)benzonitrile. According to liquid chromatography (column: CHIRALCEL® OD-RH; eluent: 90/10/0,2 pentane/methanol/triethylamine; flow rate 2 ml/min, retention time Rt 7,8 minutes) the final product contains more than 99% of the enantiomer.

1H NMR(500 MHz, DMSO-d6) δ 8,40 (singlet, 1H), 8,20 (doublet, J=8.0 Hz, 1H), 7,70 (doublet, J=8,2 Hz, 2H), 7,63 (double doublet, J=8,3, 1.1 Hz, 1H), 7,46-7,41 (multiplet, 1H), 7,31 (doublet, J=8,2 Hz, 2H), 7.23 percent (multiplet, 1H). 6,62 (singlet, 2H), 5,27 (broad singlet, 1H), 4,57 (singlet, 2H), 4.04 the (double doublet, J=10,3, 6,7 Hz, 1H), 3,93 (double doublet, J=10,3, 3,9 Hz, 1H), 2,10 (multiplet, 2H), from 0.88 (triplet, J=7,3 Hz, 3H);

Analysis. Calculated for C22H21N5ABOUT: %71,14; %N, 5,70; %N 18,85. Found: %71,10; %N, 5,98; %N, 18,96.

Example 144

2-(2-Methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine

Part a

10 ml (89,8 mmole) of propargylamine (80%solution in toluene) and of 0.60 g (3.2 mmole) of benzyltrimethylammonium dissolved in 130 ml of dichloromethane. The solution is treated with 130 ml of 50%aqueous sodium hydroxide solution and then add to it 20,0 g (73.7 mmole) 2-[2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethanol. The mixture is intensively stirred for 18 hours. Conducted after the analysis of the reaction mixture by the method of thin layer chromatography (9/1 chloroform/methanol) indicated complete reaction. React the mixture was diluted with 200 ml of water and separate the aqueous and organic phases. The aqueous fraction is extracted with additional dichloromethane (3 servings 150 ml). The organic fractions are combined together, washed with 100 ml of brine, dried over sodium sulfate, filtered and concentrated to obtain 22.7 g of 2-(2-methoxyethyl)-1-[2-(prop-2-yloxy)ethyl]-1H-imidazo[4,5-C]quinoline as an orange solid.

1H NMR(300 MHz, DMSO-d6) δ 9,15 (singlet, 1H), 8,40 (multiplet, 1H), 8,15 (multiplet, 1H), 7,73-to 7.64 (multiplet, 2H), 4,89 (triplet, J=5.3 Hz, 2H), 4,10 (doublet, J=2.4 Hz, 2H), 3,95 (triplet, J=5,1 Hz, 2H), 3,89 (triplet, J=6,9 Hz, 2H), 3,36 (triplet, J=6,9 Hz, 2H), 3,32 (singlet, 3H), 3,27 (triplet, J=6,9 Hz, 2H),

Part b

22,7 g (73.4 mmole) of 2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline are dissolved in 300 ml of chloroform and the solution is cooled in an ice bath. To the cooled solution in small portions during 30 minutes added 17.0 g (127,9 mmole) 77%3-chloroperoxybenzoic acid. Analysis by the method of thin layer chromatography (9/1 chloroform/methanol), conducted within 30 minutes after adding the acid, indicates the presence in the reaction mixture a quantity of the source material. Therefore, to the reaction mixture add 7,00 g (52,7 mmole) 77%3-chloroperoxybenzoic acid. After 2 hours the reaction mixture is heated to ambient temperature and add it to 100 ml of a saturated solution of bicarb the ATA sodium. Separate the aqueous and organic phases. The aqueous layer was extracted with additional chloroform (2 portions of 50 ml). The combined organic fraction was washed with 100 ml water, 100 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain a dark orange solid. According to PMR-spectroscopy this crude product contains less than 5% 3 chlorbenzoyl acid. Further it is used without additional purification.

1H NMR(300 MHz, DMSO-d6) δ 8,56 (singlet, 1H), 8,33 (doublet, J=7.7 Hz, 1H), 7,99 (doublet, J=7,3 Hz, 1H), 7,38-7,30 (multiplet, 2H), 4,40 (triplet, J=4,8 Hz, 2H), 3.63 doublet, J=2.1 Hz, 2H), 3,47 (triplet, J=4,9 Hz, 2H), 3,40 (triplet, J=6,9 Hz, 2H), 2,88 (triplet, J=2.0 Hz, 2H), 2,84 (singlet, 3H), 2,78 (triplet, J=6.3 Hz, 2H),

The part With

of 1.57 g (4.83 g mmole) of 2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide in the atmosphere of nitrogen dissolved in 25 ml of dichloromethane and to the solution with a syringe added dropwise to 0.80 ml (of 6.71 mmole) trichloroacetimidate. The reaction mixture is stirred for one hour, then vacuum to remove volatile products. The residue is treated with 15 ml of methanol and the result is an orange suspension. To this suspension with a syringe slowly add 25%solution of sodium methylate in methanol. The suspension turns into a dark orange solution. 1.5 hours re Klenow mixture is slowly added to 10 ml of a saturated solution of ammonium chloride. The methanol is distilled off in vacuum. The remaining aqueous solution is extracted with three portions of dichloromethane (10 ml each)and the organic fractions are combined together and washed with 10 ml water and 10 ml brine, then dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude orange solid. Recrystallization from propyl gives 0,78 g of white crystals of 2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine.

1H NMR(300 MHz, DMSO-d6) δ 8.05 (doublet, J=7,3 Hz, 1H), to 7.61 (doublet, J=7,2 Hz, 1H), 7,42 (triplet, J=7.8 Hz, 1H), 7.23 percent (triplet, J=7,3 Hz, 1H), 6,44 (broad singlet, 2H), 3.63 doublet, J=2.1 Hz, 2H), 4,78 (triplet, J=5,2 Hz, 2H), 4,11 (doublet, J=2,5 Hz, 2H), 3,91 (triplet, J=5.5 Hz, 2H), 3,83 (triplet, J=6,7 Hz, 2H), 3,37 (triplet, J=2,6 Hz, 1H), 3,30 (singlet, 3H), 3,20 (triplet, J=6,8 Hz, 2H);

MS(Cl) m/e 325 (M+H);

Analysis. Calculated for C18H20N4O2: %C 66,65; %N, 6,21; %N 17,27. Found: %66,34; %H, 6,05; %N, 16,96.

Example 145

2-Methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the main method of synthesis used in example 1, part b, carry out the oxidation of 12.0 g (44,56 mmole) of 2-(2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)acetic acid ethyl ester to 8.7 g of 2-(2-methyl-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)acetic acid ethyl ester, which represents a brown solid. This m is a material predetermined used further without additional purification.

Part b

In a round bottom flask, equipped with a magnetic stirrer, under nitrogen atmosphere load of 8.7 g (30,49 mmole) of 2-(2-methyl-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)ethyl acetate, 80 ml of anhydrous dimethylformamide and 100 ml of anhydrous toluene. To this mixture, brown in color with a syringe at ambient temperature type of 3.1 ml of phosphorus oxychloride. The reaction proceeds in several minutes, while there is weak heating of the reaction mixture. Completely, the reaction is finished after 30 minutes. Volatile products are removed under reduced pressure. The remaining brown solid product partitioned between dichloromethane and 4%aqueous sodium bicarbonate solution having a pH of about 8. The aqueous layer was extracted 5 times with dichloromethane. Organic fraction unite together, dried over anhydrous sodium sulfate, concentrated under reduced pressure, after which the product is left to dry at ambient temperature under vacuum over night. The result of 9.2 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)acetic acid ethyl ester as a brown oil.

MS(Cl) for C15H14ClN3O2m/z 304 (MN+), 262, 218.

The part With

In a round bottom flask equipped with a stirrer, a load of 9.2 g (30.5 mmole) of 2-(4-chloro-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl acetate, 200 ml of methanol and 0.4 g (3.0 mmole) of potassium carbonate. The reaction of p the color is completed under stirring at 26° C for 5 hours. The resulting solution was partitioned between brine and chloroform. The organic layer removed and the aqueous layer was extracted six times with chloroform. The organic fractions are combined together, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the total volume of the mixture to about 200 ml In the achievement of this volume is observed crystallization of the product. The flask with the reaction mixture of closed and incubated at ambient temperature for 24 hours. The resulting fine white crystals are filtered out and the result of 4.49 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)ethanol.

MS(Cl) for C13H12CIN3About m/z 262 (MH+), 218.

Part D

In a round bottom flask equipped with a stirrer, a load of 3.9 g (14.9 mmole) of 2-(4-chloro-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)ethanol and 125 ml of dichloromethane, 125 ml of 50%aqueous sodium hydroxide solution and 0.55 g (0,003 mmole) of benzyltrimethylammonium. The reaction mixture is intensively stirred at ambient temperature, then add it to 8.8 g (44,71 mmole) of solid bromohydrin cinnamic acid. After 45 minutes the solution becomes transparent, and the reaction is finished. The solution is poured into 200 ml ice water and the organic layer separated. The aqueous layer was extracted four times with dichloromethane. Organic fraction of the Aut together washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining orange oil is subjected to chromatographic purification on silica gel (eluent using first dichloromethane and then the mixture 98/2 dichloromethane/methanol). Received after such cleaning, the oil is treated with diethyl ether and after filtration of the formed solids get 4,22 g of a white solid 4-chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline.

MS(Cl) for C22H20CIN3About m/z 378 (MH+), 262, 228.

Part E.

2,12 g (5,61 mmole) of 4-chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline together with 70 ml of 7%aqueous methanolic solution of ammonia is placed in the autoclave and for 16.5 hours heated at 150°C, after which the mixture is cooled to ambient temperature. At this stage, the analysis indicates that the reaction is not completed fully. The solution is concentrated under reduced temperature to a total volume of about 10 ml, diluted with 50 ml of 7%aqueous methanolic solution of ammonia and for completion of the reaction is heated in an autoclave at 150°even for 8.5 hours. After heating the solution partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is separated. The aqueous layer was saturated with loristan sodium and then extracted three times with dichloromethane. Organic fraction unite together, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining brown solid product is recrystallized from methanol and the result 0,963 g of white solid 2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-C]quinoline-4-amine. The melting point of this substance is 111,8-112,5°C.

Analysis. Calculated for C22H22N4O: %73,72; %N, TO 6.19; %N 15,63. Found: %73,48; %N, 6,25; %N, 15,57.

1H NMR(300 MHz, DMSO-d6) δ 8,08 (doublet, J=7.5 Hz, 1H), to 7.61 (doublet, J=8,1 Hz, 1H), 7,40 (triplet, J=5.6 Hz, 1H), 7.18 in-7,30 (multiplet, 6N), 6,51 (singlet, 2H), of 6.31 (doublet, J=16.2 Hz, 1H), 6,17 (double triplet, J=15,6, a 5.3 Hz, 1H), 4,76 (triplet, J=5.0 Hz, 2H), 4,05 (doublet, J=3,9 Hz, 2H), 3,91 (triplet, J=5.6 Hz, 2H), 2,64 (singlet, 3H)

MS(Cl) for C22H22N4O m/z 259 (MH+), 243, 199.

Example 146

2-Methyl-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine

Part a

Using the main method of synthesis used in example 115, part C, 2-(2-methyl-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)acetate (of 8.47 g, 29,71 mmole) enter the 4-amino group. The resulting brown oil is treated with acetonitrile and dried, resulting in a gain 3,583 g yellowish-brown solid of 2-(4-amino-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)etelaat the A.

MS(Cl) for C15H16ClN4O2m/z 285 (MN+), 270, 199.

Part b

In the apparatus Parra download 3,61 g (12,64 mmole) of 2-(4-amino-2-methyl-1H-imidazo[4,5-C]quinoline-1-yl)acetic acid ethyl ester and 50 ml triperoxonane acid and the mixture is blown with nitrogen. To the resulting solution was added 0.5 g of platinum oxide (IV). The hydrogenation process is completed at ambient temperature for 13 days. The resulting solution is filtered, and the volatile products are removed under reduced pressure. The remaining brown oil is partitioned between dichloromethane and saturated aqueous sodium bicarbonate having a pH of about 8. Separate organic and aqueous layers. The aqueous layer was extracted four times with dichloromethane. The combined organic fractions are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining white solid product is recrystallized from a mixture of ethyl acetate/methanol (9/1) and after drying receive 0,98 g of white solid 2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)ethanol.

MS(Cl) for C13H18N4O m/z 247 (MH+), 203.

The part With

Using the main method of synthesis used in example 1, part a, conduct the reaction between 0,763 g (3,098 mmole) of 2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl)ethanol and 1.1 ml (9,29 mmole) in 80%aqueous solution of methyl propargyl in Tolu the Le and the result of 0.42 g of brown oily 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine.

MS(Cl) for C16H20N4O m/z 285 (MH+), 247, 183.

Part D

Using the main method of synthesis used in example 12, part a, when the ambient temperature is carried out the reaction between 0,396 g (1,392 mmole) of 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine and 0.17 ml (1,532 mmole) of odensala. After holding the reaction mixture for 18 hours the reaction was not yet fully completed. To complete the solution further heated for 3 hours at 50°C. the Volatile products are removed under reduced pressure. Remaining after distillation, the oil is partitioned between dichloromethane and 4%aqueous solution of sodium carbonate. The organic layer is separated. The aqueous layer was extracted three times with dichloromethane. The combined organic fractions are dried over anhydrous sodium sulfate, and the volatile products are removed under reduced pressure. The remaining oily product is subjected to chromatographic purification on silica gel (eluent is a mixture of 95/5 dichloromethane/methanol). The obtained white solid product is dissolved in 2 ml of dichloromethane and the solution is treated with 2 ml of 1M HCl in ether. Volatile products are distilled off in vacuum and the remaining solid product is recrystallized from methanol, resulting in a gain 0,1089 g of hydrochloric acid salt of 2-methyl-1-{2-[(3-phenylprop-2-inyl]oxy}ethyl)-6,7,8,9-tetrahydro-1H-imides the[4,5-C]quinoline-4-amine (HCl)1.9 in the form of hard yellow-brown substance.

Analysis. Calculated for C22H24N4O.(HCl)1,9.(H2O)0,7: %S, 59,74; %N, 6,22; %N, 12,67; %Cl, 15,23. Found: %C, 59,72; %N, 6,04; %N, 12,65; %Cl, 14/99.

1H NMR(300 MHz, DMSO-d6) δ 7,93 (singlet, 2H), was 7.36-7,40 (multiplet, 3H), 7,28-7,30 (multiplet, 2H), 4,56 (triplet, J=5.0 Hz, 2H), 4,35 (singlet, 2H), 3,88 (triplet, J=5.3 Hz, 2H), 2,92 (singlet, 3H), 2,69 (singlet, 2H), 2,60 (singlet, 3H), 1,73 (singlet, 4H)

MS(Cl) for C22H24N4O m/z 361 (MH+), 247, 199.

EDUCATION CYTOKINE IN HUMAN CELLS

Determination of the activity obtained in the invention compounds to stimulate the formation of cytokines was performed using human blood cells in vitro. The activity was evaluated based on the number of interferon and factor-α tumor necrosis (IFN and TNF, respectively)secreted into the culture medium, as described in the article of Testerman with TCS. "Induction cenina using immunomodulators Imiquimod and S-27609", published in the journal of Leukocyte Biology", 58, 365-372 (September, 1995).

Preparation of culture on the basis of blood cells

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

Preparation connections

The compounds were solubilizers in dimethyl sulfoxide (DMSO). The final concentration of DMSO in the prepared samples used for the test should not exceed 1%.

Incubation

The solution used for the test compounds (60 μmol) was first introduced in the first hole, which was in complete RPMI medium, and the remaining wells were injected solutions after serial threefold dilutions. After this was added, the suspension RMS in equal amounts so that the concentration of the analyte was within the specified limits (0,12-30 Microm). The final concentration of the suspension RMS was (1,5-2)×106cells/ml Wells were closed sterile plastic lids, gently mixed samples and kept them within 18-24 hours at 37°C in an atmosphere containing 5% carbon dioxide.

Department

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

Analysis of interferon (α) and factor-α tumor necrosis ELISA according to the method

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

The concentration of factor-α tumor necrosis was determined with an ELISA kit supplied by the firm Genzyme, Cambridge, pieces Massachusetts; R&D Systems, Minneapolis, PCs Minnesota; or firm Pharmingen, San Diego, PCs California. This method of analysis allows to determine the content of interferon in units of picograms/ml

Table 8 shows the minimum concentration of compounds in which there is the formation of interferon and tumor necrosis factor. The sign "*" means that any of the investigated concentrations of added compounds the formation of interferon and tumor necrosis factor were observed. Normally, the maximum investigated con who entrace analyte was 10 or 30 μmol.

td align="center"> 0,37
Table 8
Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
10,121,11
21,11*
30,123,33
40,12*
50,121,11
60,12*
71,110,37
81,1110
9**
101,1110
111,11*
1210*
131010
141010
150,12*
160,010,37
170,120,37
180,121,11
19*
20**

Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
210.12*
220,120,37
231,11*
240,12*
250,12*
260,12*
270,12*
2810*
29**
303,33*
31**
3210*
33**
34**
35**
36**
37**
3810*
391,11*
400,12*
411,113,33
420,37*

td align="center"> 59
Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
430,37*
450,37*
460,013,33
470,12*
480,12*
490,04*
503,33*
510,37*
521,11*
531,11*
540,12*
55**
561,1110
57*30
583,33*
1,11*
601,11*
613,33*
62*30
63**
643,33*
651,11*

Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
66**
57**
683,33*
691,11*
700,37*
713,33*
721,11*
731,11*
740,37*
75**
761,11*
770,12*
78 **
79**
80**
811,11*
82**
830,37*
840,37*
850,37*
860,37*
871,11*

*
Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
880,3730
890,3710
900,1210
910,3710
923,333,33
930,1210
940,013,33
951,11*
960,1210
971,11
980,37*
990,37*
100**
1010,0410
1020,37*
103*10
1040,1210
1050,371,11
1060,37*
1080,000170,04
1090,010,37
1103,33*

Education cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
1113,33*
112**
1131,11*
1140.120,37
1150,121,11
116**
117* *
1180,010,04
1190,010,12
1200,010,01
1210,010,04
1220,010,12
1230,1210
1241,1110
1250,010,37
1260,040,04
1270,010,12
128**
1290,010,04
1303,333,33
131*10
1320,13,33

The formation of cytokine in human cells
Non sampleThe minimum effective concentration (µmol)
InterferonThe tumor necrosis factor
1333,33*
134**
135**
138 1,11*
139**
140**
1410,120,12
1420,040,04
1431,113,33
1440,010,04

1. Imidazoquinolines having the formula (I):

where X represents-CHR3-;

R1selected from the group comprising aryl; R4-aryl;

R2selected from the group comprising a hydrogen atom; alkyl; aryl; tetrahydrofuran; alkyl-Y-alkyl; alkyl-Y-aryl; and alkyl substituted by one or more substituents selected from aryl;

R4represents an alkyl or alkenylphenol group which may be separated by one or more-O-groups;

each R3represents independently from each other hydrogen or C1-10alkyl group;

each group Y is-Oh;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

or salt of the pharmaceutical quality osnovati groups.

2. The compound or salt according to claim 1, wherein R1represents - alkyl-aryl group.

3. The compound or salt according to claim 1, wherein R1represents -(CH2)0-3is a phenyl group.

4. The compound or salt according to claim 1, wherein R1represents -(CH2)0-3-substituted phenyl group.

5. The compound or salt according to claim 1, characterized in that X represents-CH(alkyl)(alkyl) group, in which alkyl groups may be the same or may differ from one another.

6. The compound or salt according to claim 1, characterized in that X represents-CH2-CH2group.

7. The compound or salt according to claim 1, characterized in that X represents-CH(C2H5)(CH2- group.

8. The compound or salt according to claim 1, wherein R2represents a hydrogen atom.

9. The compound or salt according to claim,1, wherein R2represents an alkyl group.

10. The compound or salt according to claim 1, wherein R1represents-alkyl-O-alkyl group.

11. Imidazoquinolines having the formula (II):

where X represents-CHR3- or-CHR3is an alkyl group;

R10selected from the group comprising a hydrogen atom; aryl;

R2selected from the group comprising a hydrogen atom; alkyl; alkyl-Y-alkyl;

the value of n is 0;

each group Y represents-O-;

each R3represents independently from each other hydrogen or C1-10alkyl group; and

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

12. Connection claim 11, wherein R10represents an aryl group.

13. The compound or salt according to claim 11, wherein R10represents phenyl.

14. The compound or salt according to claim 11, wherein R10is a substituted phenyl.

15. The compound or salt according to claim 11, characterized in that X represents-CH(alkyl)(alkyl) group, in which alkyl groups may be the same or may differ from one another.

16. The compound or salt according to claim 11, characterized in that X represents-CH2-CH2group.

17. The compound or salt according to claim 11, characterized in that X represents-CH(C2H5)(CH2- group.

18. The compound or salt according to claim 11, wherein R2represents a hydrogen atom.

19. With the unity or salt according to claim 11, wherein R2represents an alkyl group.

20. The compound or salt according to claim 11, wherein R2represents-alkyl-O-alkyl group.

21. Tetrahydroisoquinoline having the formula (III):

where X represents-CHR3- or-CHR3is an alkyl group;

R1selected from the group comprising R4-aryl;

R2selected from the group comprising alkyl;

R4represents an alkyl group;

each R3represents independently from each other hydrogen or C1-10alkyl group;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

22. The compound or salt according to item 21, wherein R1represents -(CH2)0-3-substituted phenyl group.

23. The compound having the formula (IV):

where X represents-CHR3- or-CHR3is an alkyl group;

R10selected from the group comprising aryl;

R2selected from the group comprising alkyl

each R3represents independently from each other hydrogen or C1-10alkyl group;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

24. Pharmaceutical composition for the induction of the biosynthesis of cytokines containing a therapeutically effective amount of a compound or salt according to claim 1 and a pharmaceutically acceptable carrier.

25. Pharmaceutical composition for the induction of the biosynthesis of cytokines containing a therapeutically effective amount of a compound or salt according to claim 11 and a pharmaceutically acceptable carrier.

26. Pharmaceutical composition for the induction of the biosynthesis of cytokines containing a therapeutically effective amount of a compound or salt according to item 21 and a pharmaceutically acceptable carrier.

27. Method of stimulating cytokine biosynthesis in an animal's body, which consists in introducing into the animal a therapeutically effective amount of a compound or salt according to claim 1, wherein the cytokine is interferon α.

28. Method of stimulating cytokine biosynthesis in an animal's body, which consists in the introduction into the organism of the animal a therapeutically effective amount of a compound or salt according to claim 11, wherein the cytokine is interferon α.

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

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

31. A method of treating viral diseases in animals, which consists in introducing into the animal a therapeutically effective amount of a compound or salt according to item 11.

32. A method of treating neoplastic disease in animals, which consists in introducing into the animal a therapeutically effective amount of a compound or salt according to item 11.

33. Method of stimulating cytokine biosynthesis in an animal's body, which consists in introducing into the animal a therapeutically effective amount of a compound or salt according to item 21, wherein the cytokine is interferon α.

34. A method of treating viral diseases in animals, which consists in introducing into the animal a therapeutically effective amount of a compound or salt according to item 21.

35. A method of treating neoplastic disease in animals, which consists in introducing into the animal a therapeutically effective if the ESCWA compound or salt according to item 21.

36. Imidazoquinolines having the formula (V):

where X represents-CHR3- or-CHR3is an alkyl group;

R1selected from the group comprising R4-aryl;

- (CH2)1-10-C≡C-R10;

R2selected from the group comprising a hydrogen atom; alkyl; alkyl-Y-alkyl;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each R3represents independently from each other hydrogen or C1-10alkyl group;

R10selected from the group consisting of a hydrogen atom and an aryl radical;

each group Y represents-O-;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

37. Imidazoquinolines having the formula (VII):

in which X represents-CHR3- or-CHR3is an alkyl group;

R1selected from the group comprising R4-aryl;

- (CH2)1-10-C≡C-R10;

R4represents an alkyl or alkenylphenol groups, both of these groups can be separated by one or more-O - groups;

each R3represents independently from each other hydrogen or C1-10alkyl group;

each R10selected from the group consisting of a hydrogen atom and an aryl radical;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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

38. The compound having the formula (VIII):

in which X represents-CHR3- or-CHR3alkyl group;

R1selected from the group comprising R4-aryl;

- (CH2)1-10-C≡C-R10;

R2selected from the group comprising a hydrogen atom;

R4represents an alkyl group;

each R3represents independently from each other hydrogen or C1-10alkyl group;

R10selected from the group consisting of a hydrogen atom and an aryl radical;

the value of n is 0;

each R is independently selected from the group consisting of C-10 alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

R7represents tertbutylphenol or benzyl group;

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

39. The compound having the formula (IX):

where X represents-CHR3- or-CHR3is an alkyl group;

R1selected from the group comprising R4-aryl;

R2selected from the group comprising alkyl;

R4represents an alkyl or alkenylphenol group;

each R3represents independently from each other hydrogen or C1-10alkyl group;

the value of n is 0;

each R is independently selected from the group consisting of C1-10alkyl, C1-10CNS, hydroxyl groups, halogen atom and triptorelin group;

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



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention describes novel thioester-substituted imidazoquinolines and their pharmaceutically acceptable salts. Compounds are able to induce biosynthesis of cytokines in human cells that allows their using in medicine. Also, invention describes a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

3 cl, 4 tbl, 79 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel improved methods for synthesis of 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate of the formula (I) that represents a novel intermediate compound used in synthesis of the known quinolone compounds of the formula (VI) possessing antibiotic properties. In compounds of the formula (I) and (VI) R represents (C1-C4)-alkyl or (C1-C4)-halogenalkyl. Method for synthesis of compound of the formula (I) involves the following steps: (a) interaction of compound of the formula (II) with alkoxyamine or halogenalkoxyamine or their salt in the presence of a base to yield compound of the formula (III); (b) interaction of compound of the formula (III) with methanesulfonic acid to yield compound of the formula (IV); (c) hydrogenation of compound of the formula (IV) with addition of sufficient amounts of methanesulfonic acid and metal-containing hydrogenation catalyst to yield compound of the formula (I). The process can be carried out without isolation of compound of the formula (IV) (step b) adding metal-containing hydrogenation catalyst and the corresponding amount of methanesulfonic acid to compound of the formula (III) directly. Compound of the formula (VI) is prepared from synthesized compound of the formula (I) by its interaction with compound of the formula (V). Also, invention relates to novel compounds of the formula (III) and (IV).

EFFECT: improved methods of synthesis.

27 cl

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to varioline derivatives of general formula (5a), wherein R1 is selected from halogen and C1-C12-alkyl; R2 is selected from hydrogen and halogen; R3, R4, R5, R6, and R7 represent hydrogen; X1 amino group optionally substituted by C1-C12-alkoxy, benzylamino, C1-C12-alkylsulfinyl, or C1-C12-thioalkyl; X2 amino group, C1-C12-thioalkyl, C1-C12-alkylsulfinyl, or optionally C1-C12-alkoxy-substituted benzylamino; or R1 and R2 pair can be combined into condensed benzene ring system optionally substituted by C1-C12-alkoxy group. Indicated compounds exhibit antitumor activity. Invention further relates to pharmaceutical composition based on these compounds and use of these compounds to prepare drug useful in treatment of cancer. Invention also comprises a method for preparing intermediate varioline compounds. .

EFFECT: expanded synthetic possibilities in heterocyclic compounds area and increased choice of antitumor agents.

16 cl, 107 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel urea-substituted imidazoquinoline ethers depicted by general formula I: (1), in which X represents -CHR5- or -CHR5-alkyl group; R1 is selected from radicals: -R4-NR8-CR3-NR5-Z-R6-Alk, -R4-NR8-CR3-NR5-Z-R6-Ph, -R4-NR8-CR3-NR5-Z-R6-furanyl, -R4-NR8-CR3-NR5R-7, phenyl being optionally substituted by one or more substituents selected from methyl, methoxy, methylthio, cyano, hydrogen, dimethylamino, and acetyl; R2 is selected from hydrogen, alkyl, and alkyl-Y-alkyl; R3 represents =O or =S; R4 represents alkyl optionally substituted by one or several O-groups; each of R5 represents C1-C10-alkyl; R6 represents ordinary bond or alkyl; R7 forms cycle together with R5; R4 represents hydrogen, C1-C10-alkyl, or forms morpholine ring together with R8; Y represents -O-; Z ordinary bond, -CO-, or -SO2-; n=0; each of R is independently selected from C1-C10-alkyl, C1-C10-alkoxy, hydroxy, halogen, and trifluoromethyl; or pharmaceutically acceptable salt of forgoing compounds. Described are further compounds of general formula II, intermediates of compounds of general formulae III and IV, pharmaceutical compositions based on compounds I and II, which are immunomodulators for synthesis of cytokines based on compounds I and II, methods of treating viral diseases utilizing compounds I and II, and methods of treating tumor diseases utilizing compounds I and II.

EFFECT: expanded synthetic possibilities in quinoline series and increased choice of therapeutically useful compounds.

25 cl, 4 tbl, 44 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

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

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

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

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

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

35 cl, 2 tbl, 15 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzopyran-4-ones of formula , wherein R1 is benzyl, chlorobenzyl, methylbanzyl, methoxybenzyl, cyanobenzyl, etc.; R2 and R2' are independently hydrogen, C1-C4-alkyl; substituted C1-C4-alkyl; R12 is -N(R4)(CO R3); R3 is phenyl optionally substituted with C1-C4-alkyl; R4 is C1-C4-alkyl optionally substituted with amino group; R5, R6, and R7 are hydrogen; R7 is hydrogen, halogen, hydroxy, C1-C4-alkoxy, and cyano; as well as specific stereoisomers thereof and stereoisomer mixtures. Also disclosed is pharmaceutical composition based on said compounds, method for modulation of KSP kynezine activity and using of said compounds in production of drugs for treatment of cell proliferative diseases.

EFFECT: new compound with pharmaceutical activity.

19 cl, 3 dwg, 4 tbl, 26 ex

FIELD: medicine, oncology.

SUBSTANCE: claimed agent represents polysaccharides from calamus root (Acorus calamus Z.) rootstock. Said polysaccharides enhance anti-tumor and anti-metastasis activity of known cytostatic preparations.

EFFECT: new agent enhancing of anti-tumor and anti-metastasis activity of cytostatic preparations.

2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical agent suppressing tumor cell growth (cancer, carcinoma). As such agent methylated primuline derivative Thioflavin T (known as agent for amyloidosis diagnosis) is used.

EFFECT: agent causing tumor size decrease (including metastasis tumor) without allergic reactions and side effects.

5 ex

FIELD: medicine.

SUBSTANCE: method involves intraperitoneally introducing aqueous solution of 5-amino-1,2,3,4-tetrahydrophthalozine-1-4-dione sodium salt solution a at a dose of 20 mg of salt per 1 kg of mice weight once a day during 5 days.

EFFECT: enhanced effectiveness of early stage detoxication; accelerated wound healing; reduced risk of relapses.

2 tbl

FIELD: medicine.

SUBSTANCE: method involves intraperitoneally introducing aqueous solution of 5-amino-1,2,3,4-tetrahydrophthalozine-1-4-dione sodium salt solution a at a dose of 40 mg of salt per 1 kg of mice weight once a day during 5 days.

EFFECT: enhanced effectiveness in inhibiting tumor dissemination.

1 tbl

FIELD: oncology and biotechnology.

SUBSTANCE: invention concerns conjugates used for treatment of malignant tumor. Conjugate includes staphylococcal or streptococcal wild-type superantigen or modified superantigen and antibody constituent. Bacterial superantigen is modified to reduce serum reactivity with preserved its antigenic activity. Amino acid sequence of superantigen incorporates A-E regions determining binding to TCR and MHC molecules class II. Invention is directed to preparing antitumor drug and also to preparing pharmaceutical composition.

EFFECT: use of the conjugate according to invention activate immune system and, therefore, resistance of mammalian against malignant tumor.

67 cl, 11 dwg, 1 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to polynucleotides encoding polypeptide modulating cancer cell proliferation, monoclonal antibody, expression vector as well as expression vector, host cell, pharmaceutical composition and pharmaceutical agent for modulating of cancer cell proliferation. Present invention is useful in determination of abnormal cell proliferation malignancy.

EFFECT: agent and method for effective cancer disease treatment.

12 cl, 6 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: method involves exposing hypothalamus area to alternating magnetic field in ultra-low frequency bandwidth and operation field to permanent magnetic field in postoperative period in combination with adjuvant chemo radiation therapy in ablatable central nerve system tumor cases. The hypothalamus area is treated in the same way and the tumor is treated with permanent magnetic field in applying palliative chemo radiation therapy in nonablatable central nerve system tumor cases.

EFFECT: reduced risk of adverse side effects; reduced tumor size; prolonged survival period.

FIELD: medicine.

SUBSTANCE: method involves using immunoregulating antibody like antibody against B7, antibody against CD23 or antibody reducing B-cells number and antibody against CD20 first of all, in particular. The combined therapy preferably involves introducing antibody against B7 and antibody against CD20.

EFFECT: wide range of applications; enhanced effectiveness of treatment.

27 cl, 4 dwg, 3 tbl

FIELD: medicine, in particular immunogenic composition.

SUBSTANCE: claimed composition contains antigens of A and B influenza viruses, sorbed on Bifidobacterium bifidum bacterial cultures, immobilized on acceptable sorbent.

EFFECT: increased immunogenicity.

2 cl, 2 ex, 5 tbl, 2 dwg

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