2-phenyl-substituted imidazotriazinones, method for their preparing and pharmaceutical composition based on thereof eliciting property of phosphodiesterase i, ii and v inhibitor

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

 

The invention relates to new nitrogen-containing bicyclic compounds with biological activity, in particular to 2-phenylselenenyl imidazolidinone, the way they are received and medicinal product based on them having the properties of an inhibitor of phosphodiesterase I, II and V.

In lined with the patent application DE 28 11 780 described imidazolidinone, suitable as bronchodilatory substances with spasmolytic activity and inhibitory activity against phosphodiesterase responsible for the metabolism of cyclic adenosine monophosphate (camp-PDE, the item of Buvo: PDE-III and PDE-IV). The inhibitory activity against phosphodiesterase responsible for the metabolism of cyclic guanosin-monophosphate [cGMP-PDE, the item of Bobo and Reifsnider (Trends in Pharmacol. Sci. 11, 150-155, 1990): PDE-I and PDE-II and PDE-V] is not described. Not discussed any compounds that contain sulfonating in the aryl residue in the 2nd position. In addition, in the French patent FR 22 13 058, Swiss patent CH 594 671, German application DE 22 55 172 and 23 64 076 and European patent EP 000 9384 described indiso-triazinone that in the 2nd position does not include any substituted aryl residues, and is also listed as bronchodilatory agents with camp-PDE inhibitory action (inhibiting action with respect to the system of camp-PDE).

p> In the international application WO 94/28902 describes pyrazolopyrimidinone, which are suitable for the treatment of impotence.

The objective of the invention is to expand the Arsenal of nitrogen-containing bicyclic compounds with biological activity, in particular the properties of the inhibitor of phosphodiesterase I, II and V.

The problem is solved, we offer 2-phenylselenenyl imidazolidinone General formula (I)

in which

R1represents a linear alkyl containing up to 4 carbon atoms, R2represents a linear alkyl containing up to 4 carbon atoms, R3and R4represent hydrogen or linear or branched alkenyl or alkoxy containing, respectively, up to 4 carbon atoms, or represent a linear or branched alkyl chain containing up to 6 carbon atoms which may be interrupted by oxygen atom, and may have from one to three same or different of the following substituents: hydroxy, methoxy, carboxyl, linear or branched alkoxycarbonyl containing up to 4 carbon atoms and/or residues of formula-SO3H, -(A)a-NR7R8, -O-CO - NR7'R8',

where

and means the number 0 or 1,

And means balance or SO2,

R7and R 8the same or different and mean hydrogen, or mean cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl, and these heterocycles may have from one to two same or different of the following substituents: hydroxy, nitro, carboxyl, fluorine, chlorine, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of the formula -(SO2C)c- NR12R13where means the number 0 or 1, R12and R13the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms, or

R7and R8mean methoxy, or mean a linear or branched alkyl containing up to 6 carbon atoms, which in some cases has one or two, identical or different substituent: hydroxy, fluorine, chlorine, phenyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula -(CO)d-NR14R15where R14and R15the same or different and mean hydrogen, methyl or ethyl, and d means the number 0 or 1, or

R7and R8together with the nitrogen atom form morpholinyl, piperidinyl or thiazolidine ring or residue of the formula

where

R16means adored, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinil or N-methylpiperazine, or

means a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy,

R7and R8- linear or branched alkyl with 1-6 carbon atoms and/or alkyl chain radicals R3/R4may be substituted by residues from a group comprising: cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl and the remnants of the formula

where

R17means hydrogen, hydroxy, formyl, acetyl, alkoxygroup containing up to 3 carbon atoms, or a linear or branched alkyl with carbon atoms to 3, which may be substituted by 1 or 2 identical or different substituents from the group comprising hydroxyl and linear or branched alkoxy containing up to 3 carbon atoms,

these heterocycles may have from one to three, same or different, substituents: fluorine, chlorine, -SO3H, linear or branched alkyl or alkoxy containing, respectively, to 3 carbon atoms, hydroxy and/or a residue of formula-SO2-NR18R19where R18and R19the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms, and is, and

R3and R4represent a group of formula-NR20R21where R20and R21different and denote alkyl containing up to 4 carbon atoms, or

R3or R4represent substituted or represent remnants of the formula

or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, hinely, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or remnants of the formula

where

R22is the above for R16value or means formyl or acetyl,

however phenyl or heterocycle radicals R3and R4can have from one to two same or different substituents: fluorine, chlorine, triazolyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, up to 4 carbon atoms, nitro and/or a group of the formula-SO3H, -OR23, -(SO2)eNR24R25, -P(O)(OR26)(OR27), where e denotes the number 0 or 1, R23means the rest of the formula

means cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen, or a linear or branched alkyl containing up to 3 carbon atoms, which may have as the e deputies: cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, benzyloxycarbonyl or phenyl which, in turn, can be substituted one to two times, equal or different substituents: methoxy, hydroxy, fluorine or chlorine, or ukazanny alkyl which may be substituted by residues of formula-CO-NR28R29or-CO-R30where R28and R29the same or different and mean hydrogen or a linear or branched alkyl containing up to 4 carbon atoms, or R28and R29together with the nitrogen atom form morpholinyl, pyrrolidinyl or piperidinyl ring, and R30means phenyl or substituted,

R24and R25the same or different and have the above for the radicals R18and R19value

R26and R27mean hydrogen, methyl, ethyl,

and/or phenyl and/or heterocycles of the radicals R3and R4can be substituted linear or branched alkyl containing up to 3 carbon atoms, which may have as substituents hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl and/or a group of formula -(SO2R31, P(O)(OR32)(OR33or-NR34R35where R31means methyl, R2 and R33the same or different and have the above for the radicals R26and R27value

R34and R35the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy or methoxy, or

R34and R35together with the nitrogen atom form morpholinyl, thiazolidine or thiomorpholine ring, or a residue of the formula

where

R36means hydrogen, hydroxy, linear or branched alkoxycarbonyl containing up to 3 carbon atoms, or a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by a hydroxy-group, or

R3and R4together with the nitrogen atom form morpholinyl, thiomorpholine, pyrrolidinyl, piperidinyl ring, or a residue of the formula

where

R37means hydrogen, hydroxy, formyl, linear or branched acyl, alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or denotes a linear or branched alkyl containing up to 4 carbon atoms which may have from one to two same or different substituents: hydroxy, linear or branched alkoxy or alkoxycarbonyl containing the COO is responsible, to 3 carbon atoms, or a group of formula(D), NR38R39, -CO-(CH2)g-O-CO-R40, -CO-(CH2)h-OR41or-P(O)(OR42)(OR43), where g and h are identical or different and denote the number 1, 2, f denotes the number 0 or 1, D denotes a group of the formula-or-SO2, R38and R39the same or different and have the above for the radicals R7and R8value, R40means a linear or branched alkyl containing up to 3 carbon atoms, R41means a linear or branched alkyl containing up to 3 carbon atoms, R42and R43the same or different and mean hydrogen, methyl or ethyl, or

R37means the residue of formula -(CO)i-E, where i is the number 0 or 1, E means cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, the ring system can have from one to two same or different substituents: nitro, fluorine, chlorine, -SO3H, linear or branched alkoxy containing up to 3 carbon atoms, hydroxy or a residue of formula-SO2-NR44R45where R44and R45the same or different and are indicated for the radicals R18and R19value, or F means the remnants of the formula

thus formed together with the nitrogen atom heterocycles listed above for rediculous R 3and R4can have from one to three, same or different, may also genialnyh, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula-P(O)(OR46)(OR47),

where

R46and R47mean hydrogen, methyl, ethyl,

R48means hydroxy or methoxy,

j means the number 0 or 1,

and

R49and R50the same or different and have the above for the radicals R14and R15value, and/or

formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4can be substituted by linear or branched alkyl containing up to 4 carbon atoms which may have from one to three, same or different substituents: hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a residue of formula-SO3H, -NR51R52or-P(O)OR53OR54where R51and R52the same or different and denote hydrogen, phenyl, carboxyl, benzyl or a linear or branched alkyl or alkoxy containing, respectively, to 3 carbon atoms, R53and R54oz ACHAT hydrogen, methyl, ethyl, and/or the alkyl may be substituted by phenyl which, in turn, can have from one to two same or different substituents: fluorine, chlorine, hydroxy, methoxy or a group of the formula

-NR51'R52'where R51'and R52'the same or different and have the above for the radicals R51and R52value

and/or formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4may have as substituents phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, which can be linked via the N-function, this ring system in turn can be substituted by hydroxy or linear or branched alkyl or alkoxy containing, respectively, to 3 carbon atoms, or R3and R4together with the nitrogen atom form the remnants of the formula

thus R3and R4at the same time does not mean hydrogen, and in the case of non-hydrogen values of R3and R4may be the same or different,

R5represents hydrogen or a linear alkoxy containing up to 6 carbon atoms,

R6represents a linear alkoxy containing up to 6 carbon atoms, and their salts, hydrates, N-oxides and isomeric forms.

The compounds of formula (I) can things is to act in stereoisomeric forms, which are or as image and mirror image (enantiomers) or are not as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their current mixes. The racemic forms can be as diastereoisomers separated in a known manner on stereoisomeric standard components.

The compounds of formula (I) can also be in the form of salts. In the framework of the invention preferred are physiologically safe salts.

Physiologically safe salts can be salts of the inventive compounds with inorganic or organic acids. Preferred be salts with inorganic acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulphonic acids, such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methansulfonate, econsultation, vinylsulfonate, toluensulfonate or naphthalenesulfonate.

Physiologically safe salts can also be metal salts or ammonium salts of the inventive compounds. Especially preferred are NAT is eevie, potassium, magnesium or calcium salts, and also ammonium salts which are salts with ammonia or organic amines, such as ethylamine, di - or triethylamine, di - or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

Preferred are 2-phenylseleno imidazolidinone formula (I), in which

R1represents methyl or ethyl,

R2represents ethyl or propyl,

R3and R4the same or different and represent linear or branched alkyl chain containing up to 5 carbon atoms which can be substituted one to two times, equal or different way hydroxy or methoxy, or R3and R4together with the nitrogen atom form piperidinyl, morpholinyl, thiomorpholine ring, or a residue of the formula

where

R37means hydrogen, formyl, linear or branched acyl or alkoxycarbonyl containing, respectively, to 3 carbon atoms, a linear or branched alkyl containing up to 3 carbon atoms which may have from one to two same or different substituents: hydroxy, carboxyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 atoms of carbon is a, or a group of formula(D)fNR38R39or-P(O)(OR42)(OR43), where f denotes the number 0 or 1, D denotes a group of formula-CO, R38and R39the same or different and signify hydrogen or methyl, R42and R43the same or different and mean hydrogen, methyl or ethyl, or

R37means cyclopentyl,

thus formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4can have from one to two same or different, may also genialnyh, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula-P(O)(OR46)(OR47or -(CO)iNR49R50where R46and R47the same or different and mean hydrogen, methyl or ethyl, j means the number 0 or 1, and R49and R50the same or different and signify hydrogen or methyl,

and/or these heterocycles can be substituted linear or branched alkyl containing up to 3 carbon atoms which may have from one to two same or different substituents: hydroxy, carboxyl or a residue of formula-P(O)(OR53)(OR54), where R53and R54the same or different and mean hydrogen, methyl or ethyl,

and/or the heterocycles can soda is to reap as Deputy N-linked piperidinyl or pyrrolidinyl,

R5represents hydrogen,

and

R6represents ethoxy or propoxy,

and their salts, hydrates, N-oxides and isomeric forms.

Particularly preferred 2-phenylseleno imidazolidinone formula (I)selected from the group including

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of hydrochloride,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of the dihydrochloride,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of three-hydrate hydrochloride,

2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-cyclopentylpropionyl-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

5-methyl-2-(5-morpholine-4-sulfonyl)-2-ethoxyphenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

N,N-diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide,

N-propyl-4-ethoxy-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

2-phenylseleno imidazolidinone formula (I) can be obtained due to the fact that the compound of General formula (II)

in which

R1and R2have the above meaning,

and

L represents a linear or branched alkyl containing up to 4 carbon atoms,

subjected to two-stage interaction with the compound of General formula (III)

in which

R5and R6have the above meaning,

in the systems ethanol and phosphorus oxychloride/dichloroethane and the resulting compound of General formula (IV)

in which

R1, R2, R5and R6have the above meaning, is subjected to the interaction with chlorosulfonic acid, followed by the interaction of the resulting compounds of General formula (V)

in which

R1, R2, R5and R6have the above significance, with an amine of General formula (VI)

in which

R3and R4have Visayas the TES value in an inert solvent and isolation of the target product.

This method, which is more objecta of the invention, illustrated by the following reaction scheme:

As a solvent for separate stages suitable organic solvents which do not change under the reaction conditions. Here, preferably, are esiri, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or kalogeropoulou, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylene fosforos acid (hexameter), acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the mentioned solvents. Especially preferred for the first stage is ethanol, for the second stage - dichloroethane.

The temperature of the reactions, in General, can vary in a wide area. In General, work in the field of -20°to 200°C, preferably from 0°C to 70°C.

These stages of the process, in General, carried out at normal pressure. But it is also possible to conduct them when povyshen the m or at reduced pressure (for example, in the region from 0.5 to 5 bar).

The conversion of compounds of formula (V) occurs in the temperature region from 0°to room temperature and normal pressure.

Reaction with amines of General formula (VI) occurs in one of the above chlorinated hydrocarbons, preferably dichloromethane. The temperature of the reaction, in General, can vary in a wide area. In General, work in the field of -20°to 200°C, preferably from 0°C to room temperature.

The reaction, in General, carried out at normal pressure. But it is also possible to carry it out at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar).

Compounds of General formula (II) partially known or are new and can then be derived in such a way that compounds of General formula (VII)

in which

R2has the above value,

and

T represents a halogen, preferably chlorine, is first subjected to interaction with compounds of General formula (VIII)

in which

R1has the above value,

in an inert solvent, if necessary, in the presence of a base and

trimethylsilylpropyne and the resulting compounds of General formula (IX)

in which

R1and R2have the above meaning, is subjected to the interaction with the compound of the formula (X)

where L has the abovementioned meaning, in inert solvent, if necessary, in the presence of a base.

As solvent for the individual process steps suitable organic solvents which do not change under the reaction conditions. To them are preferably esiri, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, toluene, xylene, hexane, sikorksy or petroleum fractions, or kalogeropoulou, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylene fosforos acid (hexameter), acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the mentioned solvents. Especially preferred for the first stage is dichloromethane, for the second stage a mixture of tetrahydrofuran and pyridine.

As grounds, in General, suitable hydrides or alkali metal alcoholate, such as sodium hydride or tert-butyl potassium, or cyclic amines, such as Pipa is one, pyridine, dimethylaminopyridine or bonds alkylamines in which the alkyl with 1-4 carbon atoms, such as triethylamine. Preferred are triethylamine, pyridine and/or dimethylaminopyridine.

In General, the base is used in an amount of from 1 mole to 4 moles, preferably, from 1, 2 to 3 moles, based, respectively, on 1 mol of the compounds of formula (X).

The reaction temperature, in General, can vary in a wide area. In General, work in the field of -20°to 200°C, preferably from 0°to 100°C.

Compounds of General formula (VII), (VIII), (IX) and (X) are known and can be obtained by conventional methods.

Compounds of General formula (III) can be obtained in such a way that compounds of General formula (XI)

in which

R5and R6have the above meaning,

subjected to interaction with ammonium chloride in toluene and in the presence of triethylaluminum in hexane at temperatures from -20°C to room temperature, preferably at 0°C and normal pressure, and the obtained amidin enter into the reaction, if necessary, in situ, with hydrazine hydrate.

Compounds of General formula (XI) are known and can be obtained by conventional methods.

Compounds of General formula (IV) partially known or are new and can then be the floor is received by known methods (cf. David R. Marshall, Chemistry and Industry, 2 May 1983, 331-335).

Compounds of General formula (V) are new, but can be obtained from compounds of General formula (IV) based on the publication Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin, 1974, page 338-339.

Compounds of General formula (I) inhibit or one or more responsible for the metabolism of cGMP phosphodiesterase (PDE I, PDE II and PDE V). This leads to increase of cGMP level. Differential expression of RBCs in different cells, tissues and organs, as well as differential subcellular localization of this enzyme makes it possible, in connection with the inventive selective inhibitors, selective orientation of the various processes regulated by cGMP.

In addition, compounds of General formula (I) enhance the action of substances, such as EDRF (produced by the endothelium relaxing factor), ANP (trially sodium natriuretic peptide), vasodilator substances containing nitrogroup, and all other substances that are in some way as phosphodiesterase inhibitors increase the concentration of the CHM.

Therefore, they can be used in medicines for the treatment of cardiovascular diseases, for example, for the treatment of high blood pressure, neuronal hypertension, chronic and phranchesko angina, peripheral and cardiac diseases, soudo is, arrhythmias, for the treatment of thromboembolic diseases and ischemia (ischemia), such as myocardial infarction, stroke, transitory and ischemic attacks, angina pectoris, peripheral circulatory disorders, to prevent residual effects in the nasopharynx after trombosis-antibacterial therapy, skin translaminar plastic surgery, skin translaminar plastic surgery on the coronary vessels and their consequences. In addition, they can also play a role in diseases of the brain vessels. Relaxing effect on smooth muscles makes them suitable for the treatment of diseases of the urogenital system, such as prostatic hypertrophy, incontinence, and, in particular, for the treatment of erectile dysfunction and female sexual dysfunction.

Preferably the compounds of formula (I) used as inhibitor of phosphodiesterase I, II and V.

Therefore, a further object of the invention is a medicinal product which has the properties of an inhibitor of phosphodiesterase I, II and V, containing in addition to the pharmaceutically acceptable funds as active substances are compounds of the above General formula (I) or their salts, hydrates, N-oxides and isomeric forms.

The biological activity of the compounds of the above General formula (I) can be confirmed by experience.

Activity fastdie Teras (PDE)

cGMP-stimulated PDE II cGMP-inhibiting PDE III and camp - specific PDE IV were selected or from the myocardium of pigs or cattle (bulls). CA+-calmodulin - stimulated PDE I was isolated from the aorta of pigs, brain pigs or preferably from the aorta bulls. cGMP - specific PDE V was obtained from the small intestine of pigs, the aorta of swine, human platelets and preferably from aortic bulls. Purification was carried out using anyone-exchange chromatography on MonoGRPharmacia mainly by the method Mnoey and Miles D.Hoslay, Biochemical Pharmacology, Vol.40, 193-202 (1990) and .Lugman et al., Biochemical Pharmacology, Vol.35, 1743-1751 (1986).

Determination of enzyme activity produced in a test tube at 100 μl in 20 mm Tris/HCl buffer, pH 7.5, containing 5 mm magnesium chloride, 0.1 mg/ml of albumin from serum bulls and or 800 Bq3Ncamp or3Ncgmp. The final concentration of the corresponding nucleotide was 10-6mol/L. the Reaction was started by adding the enzyme, the amount of enzyme was calculated so that the time of incubation of 30 minutes, turning suffered about 50% of the substrate. To test the cGMP-stimulated PDE II as a substrate used3Ncamp was added in portion (a portion) of 10-6mol/l is not marked(not labeled) cGMP. For testing CA+-calmodulin-for what esimai PDE I in the reaction mixture was added calcium chloride (1 mm) and calmodulin in an amount of 0.1 μ M. the Reaction was stopped by adding 100 μl of acetonitrile containing 1 mm camp and 1 mm AMP. 100 μl reaction samples were separated using HPLC (liquid chromatography), and the separated products were quantitatively determined "Online" on the scintillation counter. We measured the concentration of a substance in which the reaction rate was reduced by 50%. In addition, to test used the standard sets for analysis (activity) enzymes: "Phosphodiesterase [3H]cAMP SPA enzyme assay" and the "Phosphodiesterase [3H]cGMP SPA enzyme assay " firm Amersham Life Science. The test was performed according to the method specified by the manufacturer. For determining the activity of PDE II used a test kit [3H]cAMP SPA, to the reaction solution was added 10-6M cGMP to activate the enzyme. For testing PDE I to the reaction solution was added 10-7M of calmoduline and 1 cm of calcium chloride. Testing PDE V was performed using a test kit [3H]cGMP SPA.

The inhibition of phosphodiesterase in vitro
The analyzed compound of example No.PDE I IC50[nm]PDE II IC50[nm]FDAU V IC50[nm]
16300>10002
19 200>10002
20200>10002
26100>10001
27200>10003
32100>10004
260300>100010
27550> 10003
337200>10005

Basically, the inhibition of one or more phosphodiesterase type specified increases koncentraciis cGMP. Thus compounds of interest for many types of therapy, in which increasing concentrations of cGMP can be regarded as useful.

Research actions on the cardiovascular system were conducted on SH-rats and dogs. The substance was administered intravenously or orally.

The study of the exciting erections action was carried out on live rabbits [H. Naganuma, T. Egashira, Fuji J., Clinical and Experimental Pharmacology and discrimination 20, 177-182 (1993)]. The substance was administered intravenously, orally or parenterally.

New substances, as well as their physiologically safe salts (for example, hydrochloride, maleates or lactate) can be known by the method introduced in conventional formulations (form is), such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carrier or solvent. Thus therapeutically active compound should in each case be present in a concentration of from about 0.5 to 90 wt.% of the total amount of the mixture, i.e. in amounts which are sufficient to achieve the prescribed dosing interval.

The compositions are, for example, by mixing the active substances with solvents and/or carriers, optionally using emulsifiers and/or dispersants, while, for example, when using as diluent water as an auxiliary solvent means may be used an organic solvent.

Introduction (medicines) is made in the usual way, preferably oral, transdermal (skin) or parenteral, for example, under the tongue, cheek, intravenous, nasal, rectal or inhalation.

In the case of use in humans during oral appointment of a suitable dosage ranges from 0.001 to 50 mg/kg, preferably 0.01 to 20 mg/kg parenteral purpose, as for example, through the mucous membrane of the nasal, cheek, in the form of inhalation suitable dosage ranges from 0.001 to 0.5 mg/to the.

Despite this, in some cases you want to change these quantities, namely depending on the body weight or way of introduction, from individual tolerability of the drug, the type of composition, from the reception time or interval at which it is receiving medication. So, in some cases, smaller doses than the abovementioned minimum amount, while in other cases must be exceeded above the upper limit. In the case of the introduction of large quantities it is recommended to divide them into separate doses throughout the day.

Compounds of General formula (I) suitable for use in medicine for animals (veterinary medicine). For use in medicine animal (veterinary) compounds or their non-toxic salts in the composition is introduced animals in accordance with common practice in medicine to animals (veterinary medicine). The veterinarian may determine the method of application and dosage in accordance with the form of subject treatment of the animal.

Compounds of General formula (I) belong to the category of low-toxic substances.

The following examples illustrate how to obtain 2-phenylselenenyl imidazo-triazinones the above formula (I).

The source connections

Primera

2-Butylisopropylamine acid

22,27 g (250 mm is l) D,L-alanine and 55,66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0°C. Then was added dropwise 59,75 g (550 ml) trimethylsilylpropyne, and the solution is stirred for 1 hour at room temperature and 1 hour at 40°C. After cooling to -10°With added dropwise 26,64 g (250 mmol) of chloranhydride butyric acid, and the mixture was stirred for 2 hours at -10°and one hour at room temperature.

Then, when the cooling was added dropwise 125 ml of water, and the reaction mixture is stirred for 15 minutes at room temperature. The aqueous layer was evaporated to dryness, the residue triturated with acetone, and the mother liquor is sucked off. After removal of solvent the residue chromatographic. The obtained product is dissolved in 3N sodium alkali, and the resulting solution evaporated to dryness. Add concentrated hydrochloric acid and again evaporated to dryness. The residue is stirred with acetone, filtered off from the precipitated solids, and the solvent is removed in vacuum. Gain of 28.2 g (71%) of a viscous oil, which after some time zakristallizuetsya.

200 MHz1H - NMR (DMSO-d6): 0,84, t, 3H; 1,22, m, 3H; 1,50, Gex., 2N; 2,07, t, 2H; 4,20, Quint., 1 N; 8,09, d, 1H.

Example 2A

2 Bucillamine-butyric acid

25,78 g (250 mmol) of 2-aminobutyric acid and 55,66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0°C. was added dropwise 59,75 g (550 ml) of trimethylsilyl the reed, and the solution is stirred for 1 hour at room temperature and 1 hour at 40°C. After cooling to -10°With added dropwise 26,64 g (250 mmol) of chloranhydride butyric acid, and the mixture was stirred for 2 hours at -10°and one hour at room temperature.

Then when the ice cooling was added dropwise 125 ml of water, and the reaction mixture is stirred for 15 minutes at room temperature. The organic layer is treated with sodium alkali, and organic solvent is removed in vacuum. After acidification precipitated solid is stirred (washed) 1 times with water and twice with petroleum ether and dried in vacuum at 45°C.

Gain of 29.1 g (67%) of colorless solid.

200 MHz1H - NMR (DMSO-d6): 0,88, 2T, 6N; 1,51, quart., 2N; 1,65, m, 2H; 2,09, t, 2H; 4,10, m, 1H; 8,01, d, 1H; 12,25, s, m, 1H.

Example 3A

2-Ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile, 87 g of potassium carbonate and 34.3 g (314,8 mmol) ethylbromide in 500 ml of acetone is refluxed until the next day. The solid is filtered off, the solvent is removed in vacuo, and the residue is distilled in vacuum. Receive 30.0 g (97%) of colorless liquid.

200 MHz1H - NMR (DMSO-d6): 1,48, t, 3H; 4,15, quart., 2N; 6,99, dt, 2H; 7,51, dt, 2N.

Example 4A

2-Ethoxybenzylidene hydrochloride

21,4 g (400 ml) chlorine is Yes ammonium suspended in 375 ml of toluene, and the suspension is cooled to 0°C. was added dropwise 200 ml of a 2M solution of trimethylaluminum in hexane, and the mixture is stirred at room temperature until the evolution of gas. After adding 29,44 g (200 mmol) of 2-ethoxybenzonitrile the reaction mixture is stirred until the next day when 80°With water bath.

The cooled reaction mass under ice cooling is added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred for 30 minutes at room temperature. The hard part is sucked off and washed with an equal volume of methanol. The mother liquor is evaporated, the resulting residue was stirred with a mixture of dichloromethane and methanol (9:1), the solid is sucked off and the mother liquor is evaporated. Get 30,4 g (76%) of colorless solid.

200 MHz1H - NMR (DMSO-d6): 1,36, t, 3H; 4,12, quart., 2N; 7,10, t, 1H; 7,21, d, 1H; 7,52, m, 2H; of 9.30, C, ush., 4H.

Example 5A

2-Propoxybenzene

75 g (630 mmol) of 2-hydroxybenzonitrile, 174 g (1,26 mol) of potassium carbonate and 232,2 g (1,89 mol) of propyl bromide in 1 l of acetone is refluxed until the next day. The solid is filtered off, the solvent is removed in vacuo, and the residue is distilled in vacuum.

BP.: 89°With (0.7 mbar)

Output: 95,1 g (93,7%)

Example 6A

2-Propoxybenzene hydrochloride

21,41 g (40 mmol) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5° C. and Then added dropwise to 200 ml of a 2M solution of triethylaluminum in hexane, and the mixture is stirred at room temperature until the evolution of gas. After adding to 32.2 g (200 mmol) of 2-propoxyethanol the reaction mixture is stirred until the next day when 80°With water bath. The cooled reaction mixture under ice cooling is added to a suspension of 300 g of silica gel and 2,85 l ice of chloroform and stirred for 30 minutes. The hard part is sucked off and washed with an equal volume of methanol. The solvent is distilled off in vacuum, the residue is stirred in 500 ml of a mixture of dichloromethane and methanol (9:1), the solid is filtered off and the mother liquor is evaporated. The residue is triturated with petroleum ether and sucked off. Gain of 22.3 g (52%) of the target product.

1H - NMR (200 MHz, CD3OD): 1,05 (3H); 1.85 to (sex., 2H); to 4.1 (t, 2H); 7,0-7,2 (m, 2H); 7.5 to the 7.65 (m, 2H).

Example 7A

2 Ethoxy-4-methoxybenzonitrile

30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile, of 83.4 g (603 mmol) of potassium carbonate and 32,88 g (301 mmol) brometane in 500 ml of acetone is boiled for 18 hours. After filtrowanie the solvent is removed in vacuo, and the residue purified via chromatography on silica gel (cyclohexane: ethyl acetate = 10:1). Get 35,9 g butter.

Rf= 0,37 (cyclohexane: ethyl acetate = 3:1)

200 MHz1H - NMR (CDCl3): 1,48, t, 3H; of 3.85, s, 3H; 4,12,quart., 2N; 6,46, m, 2H; of 7.48, d, 1H.

Example 8A

2 Ethoxy-4-methoxybenzamide hydrochloride

6,98 g (130 ml) of ammonium chloride are suspended in 150 ml of toluene, and the suspension is cooled to 0°C. was added dropwise 70 ml of a 2M solution of trimethylaluminum in hexane, and the mixture is stirred at room temperature until the evolution of gas. After adding to 11.56 g (65 mmol) of 2-ethoxy-4-methoxybenzonitrile the reaction mixture is stirred until the next day when 80°With water bath.

The cooled reaction mass under ice cooling is added to a suspension of 100 g of silica gel and 950 ml of dichloromethane, and the mixture is stirred for 30 minutes at room temperature. The hard part is sucked off and washed with an equal volume of methanol. The mother liquor is evaporated, the resulting residue was stirred with a mixture of dichloromethane and methanol (9:1), the solid is sucked off and the mother liquor is evaporated. The residue is triturated with petroleum ether and sucked off. Get to 7.95 g (50%) solids.

200 MHz1H - NMR (DMSO-d6): 1,36, t, 3H; of 3.84, s, 3H; 4,15, quart., 2N; of 6.71, m, 2H; 7,53, d, 1H; 8,91, C, ush., 3H.

Example 9A

2-(2-Ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Dissolve 24.4 g of N-acetyl-D,L-alanine in 200 ml of absolute tetrahydrofuran, and add 45 ml of absolute pyridine and 0.5 g of dimethylaminopyridine, heat is up to the boil and added dropwise 51,85 g (0,372 mol) of acid chloride of monoethylene ester of oxalic acid. The resulting mixture is heated for another 90 minutes at boiling, cooled, poured on ice water and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate, evaporated and dissolved in 62.5 ml of methanol. Add 9 g of sodium bicarbonate, stirred for 2.5 hours and filtered.

To a solution of 38,26 g (190,65 mmol) of the hydrochloride of 2-ethoxy-4-methoxybenzamide in 250 ml of methanol under ice cooling was added dropwise 9,54 g (190,65 mmol) of hydrazine hydrate is added and the resulting suspension is stirred for further 30 minutes at room temperature. To this reaction mixture was added the above methanol solution and stirred for 4 hours at the temperature of the water bath is 70°C. After filtration the solution is evaporated, the residue is distributed between the two solvents: dichloromethane and water, the organic layer dried over sodium sulfate, and the solvent is removed in vacuum.

The residue is dissolved in 250 ml of 1,2-dichloroethane, was added dropwise 32,1 ml (348 mmol) of phosphorus oxychloride and heated for two hours under reflux. The mixture is cooled, evaporated, dissolved in a small amount of methylene chloride, add diethyl ether and the solid is sucked off. It chromatographic on silica gel (methylene chloride/methanol 95:5), and the crystalline residue is triturated with diethyl ether.

Output: 8,1 g (14.9% of theory)

200 MHz1H - NMR (CDCl3): 1,58, t, 3H 2,62, s, 3H); 2,68, s, 3H; 4,25, square, 2H;? 7.04 baby mortality, d, 1H; 7,12, t, 1H; 7,25, dt, 1H; 8,19, DD, 1H; 10,02, s, 1H.

Example 10A

2-(2-Ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

7,16 g (45 mmol) of 2-bouteillerie acid and 10,67 g of pyridine are dissolved in 45 ml of THF, and after you add on the tip of a spatula of DMAP heated to boiling. Then slowly added dropwise 12,29 g (90 mmol) of acid chloride of monoethylene ester of oxalic acid, and the reaction mixture is boiled for 3 hours under reflux. The resulting mass is poured on ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on the rotor. The residue is dissolved in 15 ml of ethanol, added 2.15 g of sodium bicarbonate and boil for 2.5 hours. The cooled solution is filtered.

To a solution of 9,03 g (45 mmol) of the hydrochloride of 2-ethoxybenzylidene in 45 ml of ethanol under ice cooling was added dropwise 2.25 g (45 mmol) of hydrazine hydrate is added, and the resulting suspension is stirred for another 10 minutes at room temperature. To the obtained reaction mixture was added the above ethanol solution and stirred for 4 hours at the temperature of the water bath is 70°C. After filtration the solution is evaporated, the residue is distributed between the two solvents: dichloromethane and water, the organic layer dried over sodium sulfate, and the solvent is removed in vacuum.

Received osteoclastoma in 60 ml of 1,2-dichloroethane, and after adding 7.5 ml of phosphorus oxychloride boil two hours. The mixture is diluted with dichloromethane and neutralized by adding sodium hydrogen carbonate solution and solid sodium bicarbonate. The organic layer is dried, and the solvent is removed in vacuum. Chromatography with ethyl acetate and crystallization gave 4,00 g (28%) of colorless solid,

Rf= 0,42 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,56, t, 3H; 1,89, Gex., 2N; 2,67, s, 3H; to 3.00, t, 2H; 4.26 deaths, quart., 2N; 7,05, m, 2H; 7,50, dt, 1H; 8,17, DD, 1H; 10,00, s, 1H.

Example 11A

2-(2-Propoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

7,16 g (45 mmol) of 2-bouteillerie acid and 10,67 g of pyridine are dissolved in 45 ml of THF, and after you add on the tip of a spatula of dimethylaminopyridine heated to boiling. Then slowly added dropwise 12,29 g (90 mmol) of acid chloride of monoethylene ester of oxalic acid, and the reaction mixture is boiled for 3 hours under reflux. The resulting mass is poured on ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on the rotor. The residue is dissolved in 15 ml of ethanol, added 2.15 g of sodium bicarbonate and boil for 2.5 hours. The cooled solution is filtered.

The solution to 9.66 g (45 mmol) of the hydrochloride of 2-propoxybenzaldehyde in 45 ml of ethanol under ice cooling ordered the see of 2.25 g (45 mmol) of hydrazine hydrate is added, and the resulting suspension is stirred for another 10 minutes at room temperature. To this reaction mixture was added the above ethanol solution and stirred for 4 hours at the temperature of the water bath is 70°C. After filtration the solution is evaporated, the residue is distributed between the two solvents: dichloromethane and water, the organic layer dried over sodium sulfate, and the solvent is removed in vacuum.

The resulting residue is dissolved in 60 ml of 1,2-dichloroethane, and after adding 7.5 ml of phosphorus oxychloride boil two hours. The mixture is diluted with dichloromethane and neutralized by adding sodium hydrogen carbonate solution and solid sodium bicarbonate. The organic layer is dried, and the solvent is removed in vacuum. Crystallization from ethyl acetate gave 2.85 g (19,1%) yellow solid, chromatographic purification of the mother liquor gave 1.25 g (8.4%) of the target product.

Rf= 0,45 (dichloromethane/methanol = 95:5)

200 MHz1H-Yarm (CDCl3):of 1.03, t, 3H; 1,15, t, 3H; 1,92, m, 4H; 2,67, s, 3H; 3,01, t, 2H; 4,17, t, 2H; 7,09, m, 2H; 7,50, dt, 1H; 8,17, DD, 1H; 10,02, s, 1H.

Example 12A

2-(2-Ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f][1,2,4]triazine-4-one

5.50 g (34.8 mmol) of 2-bouteillerie acid and 8,19 g of pyridine are dissolved in 35 ml of THF, and after you add on the tip of a spatula of dimethylaminopyridine heated to Kipen who I am. Then slowly added dropwise 9,43 g (69 mmol) of the acid chloride of monoethylene ester of oxalic acid, and the reaction mixture is boiled for 3 hours under reflux. The resulting mass is poured on ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on the rotor. The residue is dissolved in 11 ml of methanol, add of 1.65 g of sodium bicarbonate and boil for 2.5 hours. The cooled solution is filtered.

To a solution of 7.95 g (34.5 mmol) of the hydrochloride of 2-ethoxy-4-methoxybenzamide in 35 ml of ethanol under ice cooling was added dropwise 1.73 g (34.5 mmol) of hydrazine hydrate is added and the resulting suspension is stirred for further 30 minutes at room temperature. Then to the reaction mixture was added the above methanol solution and stirred for 4 hours at the temperature of the water bath is 70°C. After filtration the solution is evaporated, the residue is distributed between the two solvents: dichloromethane and water, the organic layer dried over sodium sulfate, and the solvent is removed in vacuum.

The resulting residue is dissolved in 46 ml of 1,2-dichloroethane and after adding 5,74 ml of phosphorus oxychloride boil two hours. The mixture is diluted with dichloromethane and neutralized by adding sodium hydrogen carbonate solution and solid sodium bicarbonate. The organic layer is dried, and the solvent is removed in vacuum. Chromatography (dichloromethane/methanol = 50:1) to give 0.31 g of a 2.5%) solids.

Rf= 0,46 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): of 1.03, t, 3H; 1,58, t, 3H; 1,88, m, 2H; 2,62, s, 3H; 2,98, t, 2H; to 3.89, s, 3H; 4,25, quart., 2N; 6,54, d, 1H; 6,67, DD, 1H; 8,14, d, 1H; 9,54, s, 1H.

Example 13A

2-(2-Ethoxyphenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

depreciation is 29.06 g (167,8 mmol) 2-bouteillerie acid and 39,67 g of pyridine are dissolved in 170 ml of THF, and after you add on the tip of a spatula of dimethylaminopyridine heated to boiling. Then slowly added dropwise 45,81 g (335,5 mmol) of the acid chloride of monoethylene ester of oxalic acid, and the reaction mixture is boiled for 3 hours under reflux. The resulting mass is poured on ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on the rotor. The residue is dissolved in 15 ml of methanol, add of 7.96 g of sodium bicarbonate and boil for 2.5 hours. The cooled solution is filtered.

To a solution equal to 16.83 g (83,9 mmol) of the hydrochloride of 2-ethoxybenzylidene in 85 ml of ethanol under ice cooling was added dropwise 4,20 g (83,9 mmol) hydrazine hydrate, and the resulting suspension is stirred for another 10 minutes at room temperature. To this reaction mixture was added the above methanol solution and stirred for 4 hours at the temperature of the water bath is 70°C. After filtration the solution is evaporated, the residue is distributed between the two solvents: d what chlormethine and water, the organic layer is dried over sodium sulfate, and the solvent is removed in vacuum.

The resulting residue is dissolved in 112 ml of 1,2-dichloroethane, and after adding 14 ml of phosphorus oxychloride boil two hours. The mixture is diluted with dichloromethane and neutralized by adding sodium hydrogen carbonate solution and solid sodium bicarbonate. The organic layer is dried, and the solvent is removed in vacuum. Chromatography (dichloromethane/methanol = 50:1) network of 3.69 g (12,4%) of colorless solid.

Rf= 0,46 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): 1,32, t, 3H; 1,57, t, 3H; 1,94, m, 8H; 3,03, quart., 2N; 3,64, Quint., 1H; 4,27, quart., 2N; 7,06, d, 1H; 7,12, t, 1H; 7,50, dt, 1H; 8,16, DD, 1H; to 9.91, s, 1H.

Example 14A

4 Ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulphochloride

To 7,25 g (25.5 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it when cooled add 26,74 g (0.23 mmol) of chlorosulfonic acid. The mixture is stirred at room temperature until the next day, poured on ice water, the crystals are sucked off and dried in a vacuum desiccator.

Yield 9.5 g (97% of theory)

200 MHz1H - NMR (DMSO-d6): 1,32, t, 3H; 2,63, s, 3H; 2,73, s, 3H; 4,13, square, 2H; 7,15, d, 1H; to 7.77, m, 2H; 12,5, s, 1H.

Example 15A

4 Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulphochloride

a 2.00 g (6.4 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazine-4-she added slowly at 0°With a 3.83 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured on ice water and extracted with dichloromethane. Get 2,40 g (91%) of colorless foam.

200 MHz1H - NMR (CDCl3): of 1.03, t, 3H; 1,61, t, 2H; 1,92, Gex., 2N; 2,67, s, 3H; 3,10, t, 2H; 4,42, quart., 2N; 7,27, t, 1H; 8,20, DD, 1H; 8,67, d, 1H; 10,18, s, 1H.

Example 16A

4-Propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulphochloride

2,80 g (8.6 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-she added slowly at 0°C 5,13 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured on ice water and extracted with dichloromethane. Obtain 3.50 g (96%) of colorless foam.

Rf= 0,49 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): 1,03, 2T, 6N; 1,95, m, 4H; 2,81, s, 3H; 3,22, t, 2H; 4,11, t, 2H; 7,09 m, 1 H; 8,06, DD, 1 H; 8,21, m, 1 N; 12,0, s, 1 N.

Example 17A

4 Ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]-triazine-2-yl)benzosulphochloride

0.31 g (0.9 mmol) of 2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f][1,2,4]triazine-4-slowly add the keys at 0° With 0.54 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured on ice water and extracted with dichloromethane. Get 0,355 g (89%) of colorless foam.

Rf= 0,50 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): 1,05, t, 3H; 1,66, t, 3H; 1,95, m, 2H; 2,61, s, 3H; 3,11, t, 2H; 4,15, s, 3H; 4,40, quart., 2N; of 6.65, s, 1H; 8,72, s, 1H; 9,75, s, 1H.

Example 18A

4 Ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulphochloride

1.70 g (to 5.21 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazine-4-she added slowly at 0°to 3,12 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured on ice water and extracted with dichloromethane. Get 2,10 g (94%) of colorless foam.

200 MHz1H - NMR (CDCl3): of 1.03, t, 3H; 1,35, t, 3H; 1,62, t, 3H; 1,92, sex., 2N; 3,07, quart., 2N; 3,12, t, 2H; 4,42, quart., 2N; 7,38, d, 1H; 8,19, DD, 1H; 8,70, d, 1H; 10,08, C, ush., 1H.

Example 19A

Diethyl ether (4-piperidinylmethyl)phosphonic acid

In the reaction vessel is placed 2,11 g (528 mmol) of a 60% solution of sodium hydride in 50 ml of absolute ethanol and added dropwise 15.7 g (of 52.8 mmol) of diethyl ether metadatastorage acid. Stirred for 30 minutes at room temperature and then ordered the see of 10.1 g (52,8 mmol) 1-benzyl-4-piperidone. The resulting mixture was stirred for one hour at room temperature and one hour at boiling, evaporated, treated with water, extracted three times with dichloromethane, dried over sodium sulfate and evaporated. The remainder hydronaut in 50 ml of ethanol, 1.7 g of 10%palladium on charcoal at room temperature and a pressure of 3 bars. The catalyst was sucked off and the filtrate evaporated.

Yield: 12.5 g (100% of theory)

400 MHz1H - NMR (CDCl3): 1,13, m, 2H; 1,32, t, 6N; 1,69, DD, 2H; 1,74-1,95 m, 4H; 2,62, dt, 2H; 3,05 m, 2H; 4,1, m, 4H.

Example 20A

5-Methyl-4-peroxocarbonate

40, g (571 mmol) crotonic aldehyde is dissolved in 80 ml of acetic acid and, at 0°With added dropwise a solution of 137 g (1,99 mmol) of sodium nitrite in 300 ml of water. Stirred for 2 hours at room temperature. Diluted with 800 ml of water and extracted 3 times with dichloromethane. After drying the organic layer chromatography (cyclohexane/ethyl acetate) to obtain 13.8 g (18,9%) 5-methyl-4-peroxocarbonate.

200 MHz1H - NMR (CDCl3): 2,39, s, 3H; 10,10, s, 1H.

Example 21A

The acid chloride of 5-methyl-4-peroxocarbonates acid

13.5 g (105 mmol) of 5-methyl-4-peroxocarbonate dissolved in 200 ml of acetone and 0°add a solution 16,86 g (168 mmol) of chromium trioxide in 120 ml of 2.2 M sulfuric acid. The mixture plumage is eshivot 2 hours at 10-15° C and at room temperature until the next day. Then, when the cooling was added dropwise 100 ml of isopropanol, and after 30 minutes the solvent is removed in vacuum. The aqueous layer was extracted 3 times with ether, the organic layer is dried over magnesium sulfate, and the solvent is removed in vacuum. The residue is dissolved in 1 M sodium hydroxide solution, and the solution is extracted 3 times with ether. The aqueous layer is acidified and extracted 3 times with ether. The organic layer is dried, and the solvent is removed in vacuum. The remainder of the mix (pound) with petroleum ether and sucked off.

6,92 g of the residue and 10 ml of thionyl chloride in 20 ml of dichloromethane is boiled for 6 hours under reflux. Diluted with toluene, filtered and evaporated on the rotor. The residue is again dissolved in dichloromethane, add 10 ml of thionyl chloride and boiled for 48 hours. The solvent is removed in vacuo, and the residue is distilled in vacuum.

Get a 2.00 g (25%) of colorless crystals.

200 MHz1H - NMR (CDCl3): 2,41, C.

Example 22A

1-(5-Methyl-4-peroxocarbonate)-4-tert-butyl-oxycarbonyl-piperazine

2,75 g (14.7 mmol) of the BOC-piperazine and 1,49 g of triethylamine dissolved in 20 ml of dichloromethane and, at 0°With portions add a 2.00 g (12.3 mmol) of acid chloride of 5-methyl-4-peroxocarbonates acid. The mixture is stirred for 30 minutes at 0°and 2 hours at room temperature, razbam Aut dichloromethane and washed with water. The solvent is removed in vacuo, and the residue purified by chromatography (cyclohexane/ethyl acetate). Get 3.33 g (87%) of 1-(5-methyl-4-peroxocarbonate)-4-tert-butyl-oxycarbonyl-piperazine.

200 MHz1H - NMR (CDCl3): 1,50,, N; 2,30, s, 3H; 3,55, m, 4H; 3,78 m, 2H a 3.87, m, 2H.

Example 23A

1-(5-Methyl-4-peroxocarbonate)-piperazine triptorelin

3.12 g (10 mmol) of 1-(5-methyl-4-peroxocarbonate)-4-tert-butyl-oxycarbonyl-piperazine was dissolved in 20 ml of dichloromethane and, at 0°add 2 ml triperoxonane acid. Mixture is allowed to spontaneously warm to room temperature and stirred for 72 hours. After adding 10 ml of ether, the precipitate is sucked off and dried. Get 2,47 g (83%) of triptoreline 1-(5-methyl-4-peroxocarbonate)-piperazine.

200 MHz1H - NMR (DMSO-d6): 2,18, s, 3H; 3,18, m, 2H; 3,25, m, 2H; 3,83, m, 2H; 3,90, m, 2H; 8,89, C, ush., 2H.

Target products

Example 1

2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

0.1 g (0.26 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide dissolved in 10 ml dichloromethane and cooled to 0°C. After adding on the tip of a spatula of DMAP (dimethylaminopyridine) was added 80 mg (0,784 mmol) of N-methylpiperazine, and the reaction mixture was stirred at room te is the temperature until the next day. Dilute with dichloromethane, the organic layer washed with a solution of ammonium chloride, dried over sodium sulfate, and the solvent is removed in vacuum. The remainder chromatographic on silica gel (dichloromethane/methanol 9:1).

Yield 40 mg (34.5% of theory)

Mass spectrum: 447 (M+H); 284; 256; 224.

Example 2

2-[2-Ethoxy-5-(4-hydroxyethylpiperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 100 mg (0,784 mmol) 4-hydroxyethylpiperazine get 45 mg (36.1% of theory) of 2-[2-ethoxy-5-(4-hydroxyethylpiperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]the triazine-4-it.

Mass spectrum: 477 (M+H); 284; 256; 239.

Example 3

2-[2-Ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0.26 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 80 mg (0,784 mmol) of 4-hydroxypiperidine receive 35 mg (29,8% of theory) of 2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f]-[1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3)): to 1.61, t, 3H; 1,69, m, 2H; 1,94, m, 2H; 2,67, s, 3H; 2,70, s, 3H; 3,02, m, 2H; 3,30, m, 2H; 3,84, m, 1H; 4,37, square, 2H; 7,18, d, 1H; of 7.90,DD, 1H; charged 8.52, d, 1H; 9,73, s, 1H.

Example 4

2-[2-Ethoxy-5-(4-hydroxyethylpiperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 90 mg (0,784 mmol) of 4-hydroxyethylpiperazine, obtain 22 mg (18% of theory) of 2-[2-ethoxy-5-(4-hydroxyethylpiperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]the triazine-4-it.

200 MHz1H - NMR (CDCl3): 1,38, dt, 2H; 1,62, t, 3H; 1,82, DD, 2H; 2,35, dt, 2H; 2,78, s, 3H; 2,84, s, 3H; 3,5, d, 2H; 4,39, square, 2H; 7,21, d, 1H; 7,95, DD, 1H; 8,51, d, 1H; there is a 10.03, USS, 1H.

Example 5

2-[2-Ethoxy-5-(3-hydroxypyrrolidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 70 mg (0,784 mmol) 3-hydroxypyrrolidine, 13 mg (11.1% of theory) of 2-[2-ethoxy-5-(3-hydroxypyrrolidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazine-4-it.

Mass spectrum: 434 (M+N)

Example 6

4 Ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 70 mg (0,784 mmol) 2-(ethylamino)ethanol, obtain 23 mg (20.1% of theory) 4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazine-2-yl)benzosulfimide.

200 MHz1H - NMR (CDCl3): 1,2, t, 3H; 1,6, t, 3H; 2,17, USS, 1H; 2,69, s, 3H; 2,75, s, 3H; 3,33, m, 4H; 3,8, t, 2H; 4,36, square, 2H; 7,18, d, 1H; 7,99, DD, 1H; 8,6, d, 1H; 9,84, USS, 1H.

Example 7

N,N-Diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]-triazine-2-yl)benzosulfimide

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzene-sulfochloride and 60 mg (0,784 mmol) diethylamine receive 21 mg (18,6% of theory) of N,N-diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide.

200 MHz1H - NMR (CDCl3): 1,18, t, 6N; to 1.61, t, 3H; 2,68, s, 3H; 2,72, s, 3H; 3,29, square, 4H; 4,35, square, 2H; 7,15, d, 1H; 7,95, DD, 1H; 8,58, d, 1H; 9,8 OSS, 1H.

Example 8

2-[2-Ethoxy-5-(4-(2-pyrimidinyl)piperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 130 mg (0,784 mmol) 1-(2-pyrimidinyl)piperazine, obtain 38 mg (28.2% of theory) of 2-[2-ethoxy-5-(4-(2-pyrimidinyl)piperazine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3) 1,6, t, 3H); 2,68, s, 3H; 2,72, s, 3H; 3,12, t, 4H; 3,96, t, 4H; 4,34, square, 2H; 6,5, t, 1H; 7,18, d, 1H; 7,9, DD, 1H; 8,28, d, 2H, 8,51, d, 1H; 9,7, USS, 1H;

Example 9

2-[2-Ethoxy-5-(morpholine-4-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 70 mg (0,784 mmol) of the research obtain 28 mg (24,2% of theory) of 2-[2-ethoxy-5-(morpholine-4-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3): 1,53, t, 3H; 2,69, s, 3H; 2,72, s, 3H; 3,06, t, 4H; of 3.77, t, 4H; 4,39, square, 2H; 7,2, d, 1H; to $ 7.91, DD, 1H; 8,51, d, 1H; 9,78, USS, 1H.

Example 10

2-[2-Ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonan-6-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 100 mg (0,784 mmol) of 1,4-dioxa-6-azaspiro[4.4]nonane, receive 45 mg (35.3%) of theory) of 2-[2-ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonan-6-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3): 1,58, t, 3H; 2,02, t, 2H; 2,61, s, 3H; 2,65, s, 3H; 3,32, s, 2H; 3,41, t, 2H; 3,88, m, 4H; 4,34, square, 2H; 7,17, d, 1H; 7,92, DD, 1H; 8,51, d, 1H; 9,92, USS, 1H.

Example 11

N,N-Bis(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f]-[1,24]triazine-2-yl)benzosulfimide

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 100 mg (0,784 mmol) of bis(2-ethoxyethyl)amine, obtain 37 mg (27.5% of theory) of N,N-bis(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide.

200 MHz1H - NMR (CDCl3): 1,58, t, 3H; 2,61, s, 3H; 2,64, s, 3H; 3,3, C, 6N; of 3.46, t, 4H; 3,56, t, 4H; 4,32, square, 2H; 7,12, d, 1H; 7,95, DD, 1H; 8,51, d, 1H; 9,9, USS, 1H.

Example 12

N-(3-Isoxazol yl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 70 mg (0,784 mmol) 3-aminoisoquinoline receive 20 mg (17.2% of theory) of N-(3-isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

200 MHz1H - NMR (CDCl3): 1,6, t, 3H; 2,73, s, 3H; 2,81, s, 3H; 4,35 square, 2H; 6,6, d, 1H; 7,14, d, 1H; 8,05, DD, 1H; 8,27, d, 1H; 8,63, d, 1H; being 9.61, USS, 1H.

Example 13

2-[2-Ethoxy-5-(2-tert-butoxycarbonylmethyl-4-sulfonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triaz the h-2-yl)benzosulfimide and 170 mg (0,784 mmol) 2-tert-butoxycarbonylmethylene get 64 mg (22.2% of theory) of 2-[2-ethoxy-5-(2-tert-butoxycarbonylmethyl-4-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazine-4-it.

Mass spectrum: 563 (M+H)

Example 14

2-[2-Ethoxy-5-(4-phenylpiperazin-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 130 mg (0,784 mmol) 1-phenylpiperazine obtain 38 mg (28.3% of theory) of 2-[2-ethoxy-5-(4-phenylpiperazin-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3): 1,62, t, 3H; 2,72, s, 3H; 2,77, s, 3H; 3,25, m, 8H; to 4.38, square, 2H; 6,92, m, 2H; 7,02, d, 1H; 7.18 in-37, m, 3H; 7,94, DD, 1H; 8,55, m, 1H; 9,79, USS, 1H.

Example 15

2-[2-Ethoxy-5-(3-hydroxy-3-methoxypiperidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,261 mmol) 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 100 mg (0,784 mmol) 3-hydroxy-3-methoxypiperidine receive 30 mg (23.5% of theory) of 2-[2-ethoxy-5-(3-hydroxy-3-methoxypiperidine-1-sulfonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Mass spectrum: 478 (M+N)

Example 16

2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

of 1.23 g (3 mmol) 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]Tria is in-2-yl)benzosulfimide dissolved in 40 ml dichloromethane and cooled to 0° C. After adding on the tip of a spatula of DMAP gain of 0.90 g (of 9.00 mmol) of N-methylpiperazine, and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, the organic layer washed twice with water, dried over sodium sulfate, and the solvent is removed in vacuum. Crystallization from ether gives a 1.25 g (88%) of colorless solid.

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,59, t, 3H; 1,88, Gex., 2N; to 2.29, s, 3H; of 2.51, m, 4H; 2,63, s, 3H; to 3.00, t, 2H; is 3.08, m, 4H; 4,33, kV, 2H; 7,17, d, 1H; 7,88, DD, 1H; 8,44, d, 1H; 9,75, s, 1H.

Example 17

2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one lactate

100 mg (0,211 mg), 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it is suspended in 5 ml of ether and add 20 mg of 85% solution of lactic acid in water. Stirred for 10 minutes at room temperature and evaporated to dryness. Triturated with ether and sucked off. Obtain 110 mg (92%) lactate 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (DMSO-d6): 0,92, t, 3H; 1,22, m, 3H; 1,31, t, 3H; 1,74, m, 1H; 2,15, s, 3H; 2,38, m, 4H; 2,81, t, 2H; 2,91, m, 4H; 4,05, quart., 1H; 4,21, quart., 2N; 7,40, d,1H; a 7.85, m, 2H; 11,71, USS, 1H.

Example 18

2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-they are the azo[5,1-f] [1,2,4]triazine-4-one hydrochloride

100 mg (0,211 mmol) 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it is suspended in 5 ml of diethyl ether, added to 0.23 ml of 1 M hydrochloric acid in ether and stirred for 15 minutes at room temperature. The solvent is removed in vacuum. Obtain 110 mg (97%) of the hydrochloride of 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]-triazine-4-it.

200 MHz1H - NMR (DMSO-d6): 0,93, t, 3H; 1,35, t, 3H; 1,75, sex., 2N; 2,72, s, 3H; 2,86, m, 4H; 3,15, m, 2H; 3,45, m, 2H; 3,81, m, 2H; 4.25 in, quart., 2N; 7,45, d, 1H; 7,95, m, 2H; is 11.39, s, 1H; 11,90, s, 1H.

Example 19

2-[2-Ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

470 mg (1,14 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazine-2-yl)benzosulfimide dissolved in 20 ml of dichloromethane and cooled to 0°C. Add 390 mg (3,42 mmol) N-ethylpiperazine, and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, the organic layer washed twice with water, dried over sodium sulfate, and the solvent is removed in vacuum. Crystallization from ether gives 370 mg (66%) of colorless solid.

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,59, t, 3H; 1,88, Gex., 2N; 2,42, quart., 2N; 2,56, m, 4H; 2,63, s, 3H; to 3.00, t, 2H; 3,10, m, 4H; 4,33, quart., 2N; 7,17, d, 1H; 7,88, DD, 1H; 8,44, d, 1H; 9,75, s, 1H.

Example 20

2-[2-Ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one hydrochloride

0.35 g (0,712 mmol) 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it is suspended in 5 ml of ether and add this amount of dichloromethane, to the solution became homogeneous. Then add 0.8 ml of 1 M hydrochloric acid solution in ether, stirred for 20 minutes at room temperature and sucked off. Obtain 372 mg (99%) of the hydrochloride of 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

200 MHz1H - NMR (DMSO-d6): of 0.96, t, 3H; 1,22, t, 3H; 1,36, t, 3H; 1,82, sex., 2N; 2,61, s, 3H; 2,88, m, 2H; is 3.08, m, 6N; 3,50, m, 2H; 3,70, m, 2H; 4.25 in, quart., 2N; of 7.48, d, 1H; 7,95, m, 2H; 11,42, s, 1H; 12,45, s, 1H.

Example 21

2-[2-Ethoxy-5-(4-methyl-1-aminopiperidin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 0.04 g (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-ansolabehere and 0.03 g (0.29 mmol) of 1-amino-4-methylpiperazine receive 40 mg (83%) of 2-[2-ethoxy-5-(4-methyl-1-amino-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= ,09 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,59, t, 3H; 1,90, sex., 2N; 2,22, s, 3H); 2.40 a, m, 4H; 2,62, s, 3H; 2,71,m, 4H; 3,00, m,2H; 4,32, Quartet, 2H; 7,14, d, 1H; 8,05, DD,1H; 8,60, d,1H.

Example 22

2-[2-Ethoxy-5-(4-hydroxyethyl-1-aminopiperidin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 0.04 g (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine receive 46 mg (91%) of 2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,08 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,59, t, 3H; 1,90, sex, 2H; 2,49, m, 6N; 2,62, s, 3H; 2,71, m, 4H; to 3.00, t, 2H; 3,55, t,2H; or 4.31, quart., 2N; 7,14, d, 1H; 8,05, DD, 1H; 8,60, d, 1H.

Example 23

N,N-Bis(hydroxyethyl)aminoethyl-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 0.04 g (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 0,043 g (0.29 mmol) of N,N-bis(hydroxyethyl)aminoethylamino receive 46 mg (91%) of N,N-bis(hydroxyethyl)aminoethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

200 MHz1H NMR (CDCl 3): of 1.02, t, 3H; 1,53, t, 3H; 1,70, m, 2H; 1,86, sex., 2N; 2,9 m, N; 2,95, t, 2H; 3,09, t, 2H; 3,65, t, 4H; 4,28, quart., 2N; 7,14,d, 1H; 7,95, DD, 1H; 8,35, d, 1H.

Example 24

2-[2-Ethoxy-5-(4-dimethoxyphosphinyl-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 0.4 g (0.97 mmol) of 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide, 390 mg of triethylamine and 0,86 g (2,99 mmol) 4-dimethoxyphosphinyl-piperazine receive 321 mg (53%) of 2-[2-ethoxy-5-(4-dimethoxyphosphinyl-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]-triazine-4-it.

Rf= 0,4 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,60, t, 3H; 1,88, sex., 2N; 2,62, s, 3H; 2,75, m, 4H; 3,02, t, 2H; 3,11, m, 4H; 3,70, s, 3H; 3,75, s, 3H; 4,35, quart., 2N; 5,30, s, 2H; 7,18, d, 1H; 7,88, DD, 1H; 8,45, d, 1H; 9,71, s, 1H.

Example 25

2-[2-Ethoxy-5-(4-diethoxyphosphoryl-piperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 0.4 g (0.97 mmol) of 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 0,86 g (3.7 mmol) of 4-diethoxyphosphoryl-methyl-piperidine, get 366 mg (49%) of 2-[2-ethoxy-5-(4-diethoxyphosphoryl-piperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one is.

Rf= 0,4 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (DMSO-d6): 0,92, t, 3H; 1,20, t, 6N; 1,35, t, 3H; 1,75 m, 7H; 2,25, m, 2H; 2,82, t, 2H; 3,61, d, 2H; 3,95, Quint., 4H; 4,21, quart., 2N; 7,38, d, 1H; 7,87, m, 2H; 11,70, s, 1H.

Example 26

2-[2-Ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 531 mg (1,29 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 393 mg (3.88 mmol) of 4-hydroxypiperidine receive 400 mg (64% of theory) of 2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

200 MHz1H - NMR (DMSO-d6): 0,941, t, 3H; 1,32, t, 3H; 1,45, m, 2H; 1,71,m, 4H; 2,48, s, 3H; 2,82, t, 4H; 3,11, m, 2H; 3,55, m, 1H; 4,20, quart., 2N; 4,72, d, 1H; 7,39, d, 1H; 7,87, m, 2H; 11,70, s, 1H.

Example 27

2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 411 mg (1 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 391 mg (3 mmol) 1-hydroxyethylpiperazine, obtain 380 mg (75% of theory) of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,198 (dichloromethane/methanol = 95:5)

200 MHz1H is the Mr (CDCl 3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, Gex., 3H; 2,60, m, 7H; to 3.00, t, 2H; 3,10, m, 4H; 3,60,t, 2H; 4,36, Quartet, 2H; 7,18, d, 1H; 7,89, DD, 1H; of 8.47, d, 1H; 9,71, s, 1H.

Example 28

2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one hydrochloride

200 mg (0,39 mmol) 2-[2-ethoxy-5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it is suspended in the air, add 2 ml of 1M hydrochloric acid in ether and stirred for 20 minutes at room temperature. After removal of the solvent to obtain 209 mg (100%) of the hydrochloride of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

200 MHz1H - NMR (DMSO-d6): 0,96, t, 3H; 1,35, t, 3H; 1,70, sex., 2N; 2,59, s, 3H; 2,85, t, 2H; 2,99, t, 2H; 3,18, m, 4H; 3,59,d, 2H; 3,75, m, 4H; 4,25, quart., 2N; 7,49, d, 1H; 7,95, m, 2H; to 10.62, s, 1H; 12,31, s, 1H.

Example 29

2-[2-Ethoxy-5-(4-(3-hydroxypropyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 150 mg (from 0.37 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 158 mg (1,09 mmol) of 4-(3-hydroxypropyl)piperazine, obtain 167 mg (83% of theory) of 2-[2-ethoxy-5-(4-(3-hydroxypropyl)-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,triazin-4-it.

Rf= 0,52 (dichloromethane/methanol = 10:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,70, m, 5H; 2,62,m, 8H; to 3.00, t, 2H; 3,10, m, 4H; 3,72, t, 2H; 4,36, quart,2N; 7,18, d, 1H 7,89, DD, 1H; of 8.47, d, 1H, 9,71, s, 1H.

Example 30

N-Allyl-N-(2-hydroxyethyl)-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 420 mg (1,02 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide and 300 mg (3 mmol) of allyl(hydroxyethyl)amine receive 400 mg (82% of theory) of N-allyl-N-(2-hydroxyethyl)-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

Rf= 0,345 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,90, m, 2H; 2,22, USS, 1H; 2,62, s, 3H; 2,99, t, 2H; 3,31, t, 2H; 3,78, t, 2H; 3,92, d, 2H; 4,37, quart., 2N; 5,23, m, 2H; 5,71, m, 1H; 7,15, d, 1H; 7,98, DD, 1H; 8,56, d, 1H; 9,66, s, 1H.

Example 31

N-Ethyl-N-(2-hydroxyethyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 411 mg (1.0 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 267 mg (3 mmol) of ethyl(hydroxyethyl)amine, receive 325 mg (70% of theory) of N-ethyl-N-(2-hydroxyethyl)-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihyd is imidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

Rf= 0,29 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,20, t, 3H; to 1.61, t, 3H; 1,88, sex., 2N; 2,30, USS, 1H; 2,62, s, 3H; 2,99, t, 2H; 3,32, m, 4H; 3,78, t, 2H; of 3.80, m, 2H; 4,37, Quartet, 2H; 7,15, d, 1H; 7,98, DD, 1H; 8,56, d, 1H; 9,70, s, 1H.

Example 32

N,N-Diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 400 mg (0.97 mmol) of 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 210 mg (2,92 mmol) diethylamine receive 398 mg (89% of theory) of N,N-diethyl-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]-triazine-2-yl)benzosulfimide.

Rf= 0,49 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,20, t, 6N; 1,49, t, 3H; to 1.61, t, 3H; 1,88, sex., 2N; 2,30, USS, 1H; 2,62, s, 3H; 2,99, t, 2H; 3,32, m, 4H; 3,78, t, 2H; of 3.80, m, 2H; 4,37, quart., 2N; 7,15, d, 1H; 7,98, DD, 1H; 8,56, d, 1H; 9,70, s, 1H.

Example 33

N-(2-Methoxyethyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, according to 1.23 g (3 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 680 mg (9 mmol) (2-methoxyethyl)amine receive 900 mg (67%) of N-(2-methoxyethyl)-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo-[5,1-f]-[1,2,4]-triazine-2-yl)b is ncalculated.

Rf= 0,25 (dichloromethane/methanol = 95:5)

400 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,58, t, 3H; 1,88, sex., 2N; 2,62, s, 3H; 3,01, t, 2H; 3,18, quart., 2N; 3,30, s, 3H; 3,45, t, 2H; 4,32, quart., 2N; 5,12, t, 1H; 7,13, d, 1H; 7,97, DD, 1H; 8,53, d, 1H; 9,82, s, 1H.

Example 34

N-(2-N,N-Dimethylaminoethyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 210 mg (0.49 mmol) of 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 130 mg (9 mmol) of 2-N,N-dimethylethylamine receive 150 mg (59% of theory) of N-(2-N,N-dimethylaminoethyl)-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide.

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,62, m, 4H; 1,88, sex., 2N; 2,11,, 6N; 2,39, t, 2H; 2,63, s, 3H; 3,01, m, MN; to 4.38, quart., 2N; 7,13, d, 1H; 7,97, DD, 1H; 8,53, d, 1H; 9,82, s, 1H.

Example 35

N-[3-(1-Morpholino)propyl]-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, according to 1.23 g (3 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 1.3 g (9 mmol) of 3-(1-morpholino)Propylamine, get to 1.38 g (88%) of N-[3-(1-morpholino)propyl]-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

Rf= 0,23(dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,58, t, 3H; 1,72, m, 2H; 1,88, sex., 2N; 2,46,, 6N; 2,62, s, 3H; 3,01, t, 2H; 3,15, t, 2H; 3,71, t, 4H; 4,32, quart., 2N; 7,13, d, 1H; 7,97, DD, 1H; 8,53, d, 1H; 9,79, s, 1H.

Example 36

N-[3-(4-Methylpiperidino)propyl]-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-Digi-toimitate[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide

Similarly, on the basis of 0.04 g (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 0.05 g (0.29 mmol) of 3-[4-methylpiperazine]Propylamine, obtain 0.04 g (77%) of N-[3-(4-methylpiperidino)propyl]-4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

Rf= 0,11 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,55, t, 3H; 1,68, m, 2H; 1,88, sex., 2N; 2,27, s, 3H; 2,45, s, 8H; 2,62, s, 3H; 2,98, m, 3H; 3,10, t, 2H; of 3.46, s, 1H; 4,30, quart., 2N; 7,13, d, 1H; 7,97, DD, 1H; 8,53, d, 1H.

Example 37

2-[2-Ethoxy-5-(4-(2-methoxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 40 mg (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 40 mg (0.29 mmol) of 4-(methoxyethyl)piperazine obtain 50 mg (99% of theory) of 2-[2-ethoxy-5-(4-(2-methoxyethyl)-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]Treaty the-4-it.

Rf= 0,27 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, Gex., 2N; 2,60 m, N; 2,97, t, 2H; 3,10, m, 4H; of 3.46, t, 2H; of 3.60, s, 3H; 4,36, quart., 2N; 7,18, d, 1H; 7,89, DD, 1H; of 8.47, d, 1H; 9,71, s, 1H.

Example 38

2-[2-Ethoxy-5-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 40 mg (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 50 mg (0.29 mmol) of 4-(2-N,N-dimethylaminoethyl)piperazine obtain 50 mg (99%) 2-[2-ethoxy-5-(4-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,11 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, Gex., 3H; 2,20,, 6N; 2,42, m, 4H; 2,58, m, 4H; 2,63, s, 3H; 2,99, m, 3H; 3, 10, m, 4H; 4,36, Quartet, 2H; 7,18, d, 1H; 7,89, DD, 1H; of 8.47, d, 1H, 9,71, s, 1H.

Example 39

2-{2-Ethoxy-5-[4-(3-N,N-dimethylamino-propyl)piperazine-1-sulfonyl]phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,243 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 130 mg (0.73 mmol) of 4-(3-N,N-dimethylaminopropyl)piperazine, obtain 72 mg (54%) of 2-[2-ethoxy-5-(4-(2-N,N-dimethylaminoethyl)piperazine-1-sulfonyl)FeNi is]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,08 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, sex., 3H; 2,20,, 6N; 2,25, m, 2H; 2,38, t, 2H; 2,52, m, 4H; 2,63, s, 3H; 2,99, m, 6N; 4,33, quart., 2N; 7,18, d, 1H; 7,89, DD, 1H, of 8.47, d, 1H, 9,71, s, 1H.

Example 40

2-[2-Ethoxy-5-(4-dioxolane-piperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 100 mg (0,243 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 100 mg (0.73 mmol) of 4-dioxopyrimidine obtain 111 mg (88%) of 2-[2-ethoxy-5-(4-(dioxopyrimidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,80 m, 6N; 2,63, s, 3H; 2,99, t, 2H; 3,20, m, 4H; 3,90, 4H; 4,33, quart., 2N; 7,18, d, 1H; 7,89, DD, 1H, of 8.47, d, 1H; 9,71, s, 1H.

Example 41

2-[2-Ethoxy-5-(4-(5-methyl-4-peroxocarbonate)piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

410 mg (1.0 mmol) 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f][1,2,4]triazine-2-yl)benzosulfimide dissolved in 10 ml dichloromethane and cooled to 0°C. Add 590 mg (2.00 mmol) of 1-(5-methyl-4-peroxocarbonate)piperazine and 400 mg of triethylamine, and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, the organization is practical layer is washed with a solution of ammonium chloride, 1 M hydrochloric acid and water, dried over sodium sulfate, and the solvent is removed in vacuum. Crystallization from ether gives 448 mg (74%) of colorless solid.

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,59, t, 3H; 1,88, Gex, 2H; of 2.25, s, 3H; 2,63, s, 3H; to 3.00, t, 2H; 3,20, m, 4H; 3,90, m, 2H; was 4.02, m, 2H; 4,33 quart., 2N; 7,19, d, 1H; 7,89, DD, 1H; 8,48, d, 1H; to 9.57, s, 1H.

Example 42

2-[2-Ethoxy-5-(4-acetyl-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 40 mg (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 40 mg (0.29 mmol) of N-acetylpiperidine receive 9 mg (18% of theory) of 2-[2-ethoxy-5-(4-acetylpiperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,34 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, sex., 3H; is 2.05, s, 3H; 2,63, s, 3H; 3,00 m, 6N; 3,59, m, 2H; and 3.72, m, 2H; 4,33, quart., 2N; 7,18, d, 1H; 7,89, DD, 1H; of 8.47, d, 1H; 9,71,s, 1H.

Example 43

2-[2-Ethoxy-5-(4-formyl-piperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 40 mg (0,097 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 30 mg (0.29 mmol) of N-formylpiperazine receive 35 mg (73% of theory) of 2-[2-ATAC and-5-(4-formylpiperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,29 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; to 1.61, t, 3H; 1,87, sex., 3H; is 2.05, s, 3H; 2,63, s, 3H; 3,00 m, 6N; 3, 50, m, 2H; 3,69, m, 2H; 4,33, quart., 2N; 7,18, d, 1H; 7,89, DD, 1H; 8,00, s,1H; of 8.47, d, 1H; 9,71, s, 1H.

Example 44

2-[2-Ethoxy-5-(3-butylidene)sulfanilyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

110 mg (0.6 mmol) of 3-butylidene-hydrochloride are dissolved in 2.5 ml of pyridine and cooled to 0°C. Add 210 mg (0.5 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide, and the reaction mixture was stirred 2 hours at 0°and then at room temperature until the next day. Dilute with dichloromethane, the organic layer washed with water, dried over sodium sulfate, and the solvent is removed in vacuum. Using chromatography (dichloromethane/methanol) to obtain 16 mg (6%) 2-[2-ethoxy-5-(3-butylidene)-sulfanilyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

Rf= 0,41 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): 1,01, 2T, 6N; 1,47, sex., 2N; 1,55, t, 3H; 1,88, m, 2H; 2,04, Quint., 2N; 2,62, s, 3H; 2,98, t, 2H; 4,29, quart., 2N; to 4.41, t, 2H; 7,08, d, 1H; 7,56, s, 1H; 7,98, DD, 1H; 8,58, d, 1H; 9,79, USS, 1H.

Example 45

5-Methyl-2-[5-(4-methyl-piperazine-1-sulfonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

0,85 g(2 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide dissolved in 20 ml of dichloromethane and cooled to 0° C. After adding on the tip of a spatula of DMAP gain of 0.60 g (6,00 mmol) of N-methylpiperazine, and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, the organic layer washed with ammonium chloride solution, dried over sodium sulfate, and the solvent is removed in vacuum. Crystallization from ether gives 0,80 g (77%) of colorless solid.

Rf= 0,233 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): 1,00, t, 3H; 1,15, t, 3H; 1,87, Gex., 2N; 1,99, Gex., 2N; 2,30, s, 3H; 2,52, m, 4H; 2,62, s, 3H; 2,99, t, 2H; 3,10, m, 4H; 4,21, t, 2H; 7,17, d, 1H; 7,87, DD, 1H; 8,48, d, 1H; 9,70, s, 1H.

Example 46

5-Methyl-2-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one hydrochloride

22 mg (0.045 mmol) of 5-methyl-2-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-she dissolved in 2 ml of ether and 1 ml of dichloromethane and add 0.1 ml of 1 M hydrochloric acid in ether. After 20 minutes, the precipitation is sucked off and dried.

200 MHz1H - NMR (CDCl3): 0,95, t, 3H; 1,75 m, 2H; 2,56, s, 3H; 2,75, m, 4H; 2,97, t, 2H; 3,15, m, 2H; 3,44, m, 2H; 3,81, m, 2H; 4,15, t, 2H; 7,47, d, 1H; 7,95, m, 2H; 11,12, s, 1H; 12,22, s, 1H.

Example 47

2-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similar is cnym way on the basis of 850 mg (2 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 610 mg (6 mmol) of 4-hydroxypiperidine receive 736 mg (75% of theory) of 2-[5-(4-hydroxypiperidine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it

Rf= 0,07 (dichloromethane/methanol = 95:5)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,16, t, 3H; 1,80 m, N; 2,65, s, 3H; 3,00, m, 4H; 3,32, m, 2H; 3,85, m, 1H; 4,22, t, 2H; 7,17, d, 1H; 7,89, DD, 1H; 8,50, d, 1H; 11,70, s, 1H.

Example 48

2-[5-(4-Hydroxyethylpiperazine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 35 mg (0.3 mmol) 4-hydroxyethylpiperazine, obtain 41 mg (82% of theory) of 2-[5-(4-hydroxyethylpiperazine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it

Rf= 0,52 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): 1,001, t, 3H; 1,16, t, 3H); 1.60, m, 4H; 1,82, m, 5H; 2,31, t, 2H; 2,62, s, 3H; 2,98, t, 2H; 3,48, d, 2H; 3,85, d, 2H; 4,21, t, 2H; 7,17, d, 1H; 7,88, DD, 1H; 8,45, d, 1H; 9,71, s, 1H.

Example 49

2-[5-(4-(2-Hydroxyethyl)piperazine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, based on the C 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 39 mg (3 mmol) 4-hydroxyethylpiperazine, receive 50 mg (96% of theory) of 2-[5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-MN-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,43 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,88, m, 2H; 2,00, m, 2H; 2,62, m, N; to 3.00, t, 2H; 3,07, m, 4H; to 3.58, t, 2H; to 4.23, t, 2H; 7,19, d, 1H; 7,88, DD, 1H; 8,43, d, 1H; 9,85, s, 1H.

Example 50

N-(1,1-Dioxotetrahydrofuran-1λ6-thiophene-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 41 mg (3 mmol) 2-aminosulfonyl receive 8 mg (14% of theory) of N-(1,1-dioxotetrahydrofuran-1λ6-thiophene-3-yl)3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,49 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,85, m, 2H; 1,99, m, 2H; 2,30, m, 1H; 2,50, m, 1H; 2,62 s, 3H); 2.95 points, m, 4H; 3,21, m, 1H; 4,20, m, 3H; 5,98, s, 1H; 7,18, d, 1H; 7,98, DD, 1H; 8,51, d, 1H; 9,71, s, 1H.

Example 51

N-(2-Dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-digidroid is zo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 31 mg (0.3 mmol) 1,1,4-trimethylaminoethyl, obtain 39 mg (79% of theory) N-(2-dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f|-[1,2,4]triazine-2-yl)-4-propoxybenzaldehyde.

Rf= 0,28 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,88, m, 2H; 2,01, m, 2H; 2,25,, 6N; 2,50, t, 2H; 2,62 s, 3H); 2,82, s, 3H; 3,01, t, 2H; 3.18, t, 2H; 4,21, t, 2H; 7,16, d, 1H; to $ 7.91, DD, 1H; 8,50, d, 1H; 9,70, s, 1H.

Example 52

N-(3-Morpholine-4-yl-propyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 43 mg (0.3 mmol) of 1-(3-aminopropyl)of the research, obtain 52 mg (97% of theory) of N-(3-morpholine-4-ylpropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,33 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H); 1.71, m, 2H; 1,93, m, 4H; 2,43, m, 6N; 2,62 s, 3H); 2,98, t, 2H; 3,12, t, 2H; 3.70, m, 4H; 4,21, t, 2H; 7,15, d, 1H; of 7.96, DD, 1H; 8,55, d, 1H; 9,85, s, 1H.

Example 53

N,N-Bis(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-b is solarpowered and 32 mg (0.3 mmol) of bis(hydroxyethyl)amine, obtain 34 mg (69% of theory) of N,N-bis(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,36 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,85, m, 2H; 1,97, m, 2H; 2,60, s, 3H; 2,98, t, 2H; 3,33, t, 4H; 3.87, t, 4H; 4,20, t, 2H; 7,15, d, 1H; 7,92, DD, 1H; 8,49, d, 1H; 9,85, s, 1H.

Example 54

N-(3-Hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 37 mg (0.3 mmol) of 3-hydroxybenzylidene receive 4 mg (8% of theory) N-(3-hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-1]-[1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,43 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,13, t, 3H; 1,83, m, 2H; 1,96, m, 2H; 2,59, s, 3H; 2,96, t, 2H; 4,16, m, 4H; of 5.05, t, 1H; 6,52, s, 1H; 6,70, m, 2H; 7,06, m, 2H; 7,93, DD, 1H; to 8.41, d, 1H; 9,77, s, 1H.

Example 55

N-Ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 27 mg (0.3 IMO the b) ethyl(hydroxyethyl)amine, get 18 mg (38% of theory) of N-ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzene-sulphonamide.

Rf= 0,48 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15,2 t, 6N; 1,75, s, 2H; 1,85, m, 2H; 1,98, m, 2H; 2.40 a, s, 1H; 2,62, s, 3H; 2,99, t, 2H; 3,32, m, 4H; 3,90, quart., 2N; 4,21, quart., 2N; 7,15, d, 1H; 7,95, DD, 1H; 8,55, d, 1H; 9,73, s, 1H.

Example 56

N-(3-Ethoxypropan)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 31 mg (0.3 mmol) (3-ethoxypropan)amine, obtain 47 mg (96%) of N-(3-ethoxypropan)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,60 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, m, 6N; 1,89, m, 7H; 2,62, s, 3H; to 3.00, t, 2H; 3,12, quart., 2N; of 3.46, m, 4H; 4.20, t, 2H; 5.52, m, 1H; 7,15, d, 1H; 7,98, DD, 1H; 8.55, d, 1H; 9,85, s, 1H.

Example 57

2-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 212 mg (0.5 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 152 mg (1.5 mmol who) 4-hydroxypiperidine, receive 125 mg (50% of theory) of 2-[5-(4-hydroxypiperidine-1-sulfonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,07 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): 1,05, t, 3H; 1,18, t, 3H; 1,98, m, 8H; 2,71, s, 3H; 3,10, m, 2H; 3,28, m, 4H; 3,88, m, 1H; 4,28, t, 2H; 7,21, d, 1H; 7,97, DD, 1H; 8,45, d, 1H; 10,45, s, 1H.

Example 58

3-(5-Methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-4-propoxy-N-(pyridin-4-yl)-benzosulfimide

Similarly, on the basis of 85 mg (0.2 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 56 mg (0.6 mmol) of 4-aminopyridine, after 18 hours boiling under reflux in 1 ml of tetrahydrofuran obtain 24 mg (25% of theory) of 3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[a 5.1-1]-[1,2,4]triazine-2-yl)-4-propoxy-N-(pyridin-4-yl)-benzosulfimide.

Rf= 0,13 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,09, t, 3H; 1,90, m, 4H; 2,60, s, 3H; 2,99, t, 2H; 4,16, t, 2H; 7,05, d, 2H; 7,15, d, 1H; 7,88, d, 2H; 8,05, DD, 1H; to 8.41, d, 1H,

Example 59

N,N-Diethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 22 mg (0,6 shall mol) of diethylamine, obtain 42 mg (92% of theory) of N,N-diethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,64 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,18, 2T, N; 1,92, hex., 4H; 2,62, s, 3H; to 3.00, t, 2H; 3,29, quart., 4H; 4,21, t, 2H; 7,13, d, 1H; 7,93, DD, 1H; 8,51, d, 1H; 9,85, s, 1H.

Example 60

1-[3-(5-Methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzazolyl]-piperidine-4-carboxylic acid

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 14 mg (0.6 mmol) piperidinecarboxylic acid in 1 ml of a mixture of THF and water (1:1) from 26.5 mg of sodium carbonate, obtain 21 mg (41%) of 1-[3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzazolyl]-piperidine-4-carboxylic acid

Rf= 0,28 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): 0,90, t, 3H; 1,04, t, 3H; 1,80, m, 4H; 2,21, m, 2H; of 2.51, s, 3H; 2,85, m, 2H; 3,56, m, 6N; 4,10, t, 2H; 7,12, d, 1H; 7,71, DD, 1H; 8,10, d, 1H; of 10.72, USS, 1H.

Example 61

5-Methyl-2-[5-(morpholine-4-sulfonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-bensalah the chloride and 26 mg (0.3 mmol) of the research, obtain 34 mg (71%) of 5-methyl 2-[5-(morpholine-4-sulfonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,64 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,16, t, 3H; 1,89, Gex., 2N; 2,00, Gex., 2N; 2,63, s, 3H; 3,02, m, 4H; 4,25, t, 2H; 7,19, d, 1H; 7,89, DD, 1H; 8,48, d, 1H; 9,78, s, 1H.

Example 62

N-(2-Hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 23 mg (0,63 mmol) of methyl(hydroxyethyl)amine, receive 25 mg (54%) of N-(2-hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,53 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): 1.01, t, 3H; 1,15, t, 3H; 1,82, m, 2H; 1,99, Gex., 2N; 2,40, USS, 1H; 2,62, s, 3H; 2,89, s, 3H; 2,99, t, 2H; 3,21, t, 2H; 3,80, USS, 2H; 4.21, t, 2H; 7,16, d, 1H; 7,92, DD, 1H; 8,50, d, 1H; 9,79, s, 1H.

Example 63

N-(2-Hydroxyethyl)-N-propyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-1][1,2,4]triazine-2-yl)-benzosulfimide and 31 mg (0.6 mmol) propyl(hydro shall Sitel)amine receive 20 mg (40%) of N-(2-hydroxyethyl)-N-propyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,52 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): 0,90, t, 3H; of 1.01, t, 3H; 1,15, t, 3H; 1,52, m, 2H; 1,88, m, 2H; 2,00, m, 2H; 2.40 a, s, 1H; 2,63, s, 3H; 3,01, t, 2H; 3,22, m, 4H; 3,80, quart., 2N; 4,21, t, 2H; 7,15, d, 2H; 7,95, DD, 1H; 8,55, d, 1H; 9,75, s, 1H.

Example 64

N-[2-(3,4-Acid)ethyl)]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 59 mg (0.3 mmol) N-methyl-(3,4-acid)-ethylamine, receive 45 mg (78%) of N-[2-(3,4-acid)ethyl)]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,35 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): 0,90, t, 3H; of 1.07, t, 3H; 1,78, m, 2H; 1,92, m, 2H; to 2.55, s, 3H; 2,73, s, 3H; 2,78, m, 2H; 2,89, t, 2H; 3,23, t, 2H; of 3.80, s, 6N; 4,15, t, 2H; 6,65, m, 3H; 7,05, d, 1H; 7,75, DD, 1H; to 8.41, d, 1H; 9,67, s, 1H.

Example 65

N-Allyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 31 mg (0.3 mmol) of allyl(hydroxyethyl)amine, obtain 34 mg (70%) of N-allyl-N-(hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,52 (dichloromethane/methanol = 9:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,85, m, 2H; 1,99, m, 2H; 2,38, USS, 1H; 2,63, s, 3H; to 3.00, t, 2H; 3,32, t, 2H; 3,86, t, 2H; 3,90, d, 2H; 4.25 in, t, 2H; to 5.21, m, 2H; 5,71, m, 1H; 7,15, d, 1H; 7,95, DD, 1H; 8,55, d, 1H; 9,77, C, 1H.

Example 66

N-Allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 38 mg (0.3 mmol) of allyl(cyclopentyl)amine obtain 33 mg (64%) of N-allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazine-2-yl)-4-propoxy-benzosulfimide.

Rf= 0,43 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,15, t, 3H; 1,53, m, N; 2,00, m, 4H; 2,63, s, 3H; to 3.00, t, 2H; of 3.80, m, 2H; 4,21, t, 2H; 5,20, m, 2H; 5,88, m, 1H; 7,12, d, 1H; 7,95, DD, 1H; 8,55, d, 1H; 9,75, s, 1H.

Example 67

N-Allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-[1,2,4]-triazine-2-yl)-4-propoxy-benzosulfimide

Similarly, on the basis of 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 26 mg (0.3 mmol) of allyl(ethyl)amine receive 30 mg (64%) of N-allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazine-2-yl)-4-prop is XI-benzosulfimide.

Rf= 0,44 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H); 1.15, t, 6N; 1,89, m, 2H; 2,01, m, 2H; 2,63, s, 3H; to 3.00, t, 2H; 3,27, quart., 2N; a 3.87, d, 2H; to 4.23, t, 2H; 5,20, m, 2H; 5,72, m, 1H; 7,15, d, 1H; 7,95, DD, 1H; 8,55, d, 1H; 9,80, s, 1H.

Example 68

2-[2-Ethoxy-4-methoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f)[1,2,4]triazine-4-one

20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide dissolved in 0.5 ml of dichloromethane, add on the tip of a spatula of dimethylaminopyridine and 14 mg (0,136 mmol) of N-methylpiperazine, and the reaction mixture is stirred until the next day at room temperature. After purification on siegele get to 12.8 mg (55%) of 2-[2-ethoxy-4-methoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,22 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): 0,94, t, 3H; 1,55, t, 3H; 1,80, m, 2H; 2,24, s, 3H; 2,42, t, 4H; to 2.55, s, 3H; 2,92, t, 2H; 3,19, t, 4H; 3,91, s, 3H); 4.25, quart., 2N; 6,48, s, 1H; 8,57, s, 1H; 9,54, s, 1H.

Example 69

2-[2-ethoxy-5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-4-methoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-Ben is alcolholic and 18 mg (0.14 mmol) 4-hydroxyethylpiperazine, get 11 mg (46%) of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-4-methoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,34 (dichloromethane/methanol = 15:1)

200 MHz1H - NMR (CDCl3): 0,94, t, 3H; 1,55, t, 3H; 1,80, m, 3H; 2,52, m, N; 2,92, t, 2H; 3,20, t, 4H; 3,44, t, 2H; to 3.92, s, 3H; 4,25, quart., 2N; of 6.49, s, 1H; 8,56, s, 1H; 9.55, s, 1H.

Example 70

4 Ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide

Similarly, on the basis of 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 12 mg (0.14 mmol) of ethyl(hydroxyethyl)amine, receive 8 mg (34%) 4 ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide.

Rf= 0,45 (dichloromethane/methanol = 15:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,18, t, 3H; 1,61, t, 2H; 1,88, m, 2H; 2,39, USS, 1H; 2,65, s, 3H; to 3.00, t, 2H; 3,38, quart., 2N; 3,45, t, 2H; 3,78, m, 2H; 4,01, s, 3H; 4,20, quart., 2N; 6,58, s, 1H; 8,67, s, 1H; being 9.61, s, 1H.

Example 71

4 Ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide

Similarly, on the basis of 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]Treaty the-2-yl)-benzosulfimide and 19 mg (0.14 mmol) 4-ethoxyaniline, get 7 mg (34%) 4 ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide.

Rf= 0,36 (dichloromethane/methanol = 20:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,33, t, 3H; 1,59, t, 3H; 1,86. Gex., 2N; 2,62, s, 3H; 3,02, t, 2H; 3,92, quart., 2N; 4,11, s, 3H; or 4.31, quart., 2N; 6,58, s, 1H; 6,72, d, 2H; 6,88, USS, 1H; 6,99, d, 2H; 8,50, s, 1H; 9,59, s, 1H.

Example 72

4 Ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-benzosulfimide

0.64 g (1.5 mmol) 4-ethoxy-3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)benzosulfimide dissolved in 20 ml of dichloromethane and cooled to 0°C. After adding on the tip of a spatula of dimethylaminopyridine added 0.40 g (4,50 mmol) 2-(ethylamino)-ethanol, and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, the organic layer washed with water, dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography (dichloromethane/methanol = 95:5) gives 0,454 g (63%) of colorless solid.

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,20, t, 3H; 1,35, t, 3H; to 1.61, t, 3H; 1,88, sex., 2N; 2,25, USS, 1H; 3,01, m, 4H; 3,32, m, 4H; 3,70, m, 2H; of 3.80, m, 2H; 4,37, quart., 2N; 7,15, d, 1H; 7,98, DD, 1H; 8,56, d, 1H; 9,70, s, 1H.

Example 73

N-(2-Methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]-triazine-2-yl)-4-ethoxy-benzosulfimide

Similarly, on the basis of 40 mg (0,094 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 21 mg (0,282 mmol) of 2-methoxyethylamine receive 15 mg (34%) of N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide.

Rf= 0.2 (ethyl acetate/cyclohexane = 2:1)

200 MHz1H - NMR (CDCl3): 0,97, t, 3H; 1,25, t, 3H; 1,53, t, 3H; 1,82, sex., 2N; 2,97, m, 4H; 3,11, m, 2H; 3,22, s, 3H; 3,39, t, 2H; 4,37, quart., 2N; 5,00, t, 1H; 7,17, d, 1H; 7,97, DD, 1H; 8,53, d, 1H; 9,82, s, 1H.

Example 74

N,N-Bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide

Similarly, on the basis of 40 mg (0,094 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 38 mg (0.28 mmol) of bis(methoxyethyl)amine, obtain 17 mg (34%) of N,N-bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide.

Rf= 0,34 (ethyl acetate/cyclohexane = 2:1)

200 MHz1H - NMR (CDCl3): 0,97, t, 3H; 1,27, t, 3H; 1,53, t, 3H; 1,80, sex., 2N; 2,95, m, 4H; 3,22,, 6N; 3,39, m, 4H; 3,49, m, 4H; 4,27, quart., 2N; 7,17, d, 1H; 7,97, DD, 1H; 8,53, d, 1H; 9,82, s, 1H.

Example 75

2-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-ethoxyphenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 640 mg (1.5 mmol) 4-ethoxy-3-(5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 460 mg (4.5 mmol) 4-hydroxypiperidine, obtain 485 mg (66%) of 2-[5-(4-hydroxypiperidine-1-sulfonyl)-2-ethoxyphenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,37 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): of 1.02, t, 3H; 1,32, t, 3H; 1,60, t, 3H; 1,80, m, 7H; 2,97, m, 6N; 3,30, m, 2H; 3,82, m, 1H; 4,34, quart., 2N; 7,17, d, 1H; of 7.90, DD, 1H; 8,45, d, 1H; 9,75, s, 1H.

Example 76

2-[5-(4-Hydroxyethylpiperazine-1-sulfonyl)-2-ethoxy-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

Similarly, on the basis of 40 mg (0,094 mmol) 4-ethoxy-3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 33 mg (0.28 mmol) of 4-hydroxyethylpiperazine, obtain 23 mg (48%) of 2-[5-(4-hydroxyethylpiperazine-1-sulfonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,38 (dichloromethane/methanol = 10:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,33, t, 3H; 1,60, t, 3H; 1,80, m, 8H; 2,41, m, 2H; 3,00, m, 4H; 3,56, m, 4H; 4,35, quart., 2N; 7,17, d, 1H; 7,88, DD, 1H; 8,45, d, 1H; 9,71, s, 1H.

Example 77

2-[2-Ethoxy-5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Analogion the m way on the basis of 40 mg (0,094 mmol) 4-ethoxy-3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 37 mg (0.28 mmol) of 4-hydroxyethylpiperazine receive 35 mg (71%) of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)piperazine-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,65 (dichloromethane/methanol = 10:1)

Example 78

2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one

Similarly, on the basis of 640 mg (1.50 mmol) of 4-ethoxy - 3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 450 mg (4.5 mmol) 4-methylpiperazine, obtain 495 mg (71%) of 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

Rf= 0,30 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,35, t, 3H; to 1.61, t, 3H; 1,89, sex., 2N; 2,31, s, 3H; 2,53, m, 4H; 3,05 m, 8H; 4,35, quart., 2N; 7,17, d, 1H; 7,89, DD, 1H; 8,48, d, 1H; 9,65, s, 1H.

Example 79

2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one hydrochloride

300 mg (0.61 mmol) of 2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-she dissolved in a mixture of ether and dichloromethane and add 2 ml of 1 M hydrochloric acid in ether. After 20 minutes you who awsi the precipitate is sucked off and dried.

200 MHz1H - NMR (DMSO-d6): 0,95, t, 3H; 1,32, 2T, 6N; 1,80, sex., 2N; was 2.76, m, 4H; 3,01, m, 4H; 3,15, m, 2H; 3,44, m, 2H; 3,81, m, 2H; 4.25 in, quart., 2N; 7,49, d, 1H; 7,95, m, 2H; 11,25, s, 1H; 12,30, s, 1H.

Example 80

N-(3-Morpholine-4-yl-propyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide

Similarly, on the basis of 640 mg (1.5 mmol) 4-ethoxy-3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 650 mg (4.5 mmol) of 1-(3-aminopropyl)of the research, get 476 mg (59%) of 3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-N-(3-morpholine-4-yl-propyl)-4-ethoxy-benzosulfimide.

Rf= 0,18 (dichloromethane/methanol = 19:1)

200 MHz1H - NMR (CDCl3): is 1.01, t, 3H; 1,32, t, 3H; 1,60, t, 3H; 1,70, m, 3H; 1,89, sex., 2N; 2,43, m, 7H; 3,01, m, 4H; 3,15, t, 2H; 3,70, m, 4H; 4,35, quart., 2N; 7,15, d, 1H; 7,95, DD, 1H; 8,55, d, 1H; 9,82, s, 1H.

Example 81

N-(2-Hydroxyethyl)-N-propyl-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f] [1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide

Similarly, on the basis of 640 mg (1.5 mmol) 4-ethoxy-3-(5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide and 464 mg (4.5 mmol) propyl(hydroxyethyl)amine, receive 600 mg (81%) of N-(2-hydroxyethyl)-N-propyl-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)-4-ethoxy-benzosulfimide.

R = 0,73 (dichloromethane/methanol = 10:1)

200 MHz1H - NMR (CDCl3): of 0.91, t, 3H; of 1.01, t, 3H; 1,32, t, 3H; 1,62, m, 5H; 1,88, m, 2H; 2,32, s, 1H; 3,01, m, 4H; 3,22, m, 4H; of 3.80, m, 2H; 4,35, t, 2H; 7,15, d, 2H; 7,95, DD, 1H; 8,55, d, 1H; 9,75, s, 1H.

Sulfonamides are given in the following tables 1,2,3,4 and 6 were obtained using automated parallel synthesis of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f)[1,2,4]triazine-2-yl)-benzosulfimide and the appropriate amine according to one of the following three standard techniques.

Sulfonamides, are shown in table 5 were obtained in a similar manner using automated parallel synthesis of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-δ][1,2,4]triazine-2-yl)-benzosulfimide and the appropriate amine.

The purity of the final product was determined by HPLC (high performance liquid chromatography), their characteristics were obtained by measuring parameters of liquid chromatography and mass spectrum. The content of the target substance according to HPLC - MS (mass spectrum) are given in tables in the column "HPLC" in percent. The standard technique And has been applied in the case of amines with acid function, the standard technique In the case of amines with a neutral function, the standard technique in the case of amines with an additional main function.

In some cases, hydrogen atoms are not from brainy in the structural formula, tables 1, 2, 3, 4, 5 and 6. Therefore, the nitrogen atom with the free valence should be considered as a residue NH.

Standard procedure a: Reaction of amines with acid function. First mix of 0.05 mmol amine, 0,042 mmol of sulfochloride and 0.10 mmol of sodium carbonate, and the pipette manually add 0.5 ml of a mixture of THF/water. After keeping the mixture for 24 hours at room temperature, add 0.5 ml of 1 M solution of sulfuric acid and filtered (pass) through a two-phase (double-layer) cartouche (500 mg of Extrelut (upper phase) and 500 mg of silica, eluent ethyl acetate). After evaporation of the filtrate in vacuo get target audiences.

Standard method: Reaction of amines with a neutral function. First, in the reaction vessel make 0.125 mmol amine and with the help of a synthesizer type of pipette, 0.03 mmol of sulfochloride in the form of a solution in dichloroethane. After 24 hours, to the mixture is added 0.5 ml of 1 M sulfuric acid and filtered through a two-phase (double-layer) cartouche (500 mg of Extrelut (upper phase) and 500 mg of silica, eluent ethyl acetate). The filtrate is evaporated in vacuum.

Standard method: Reaction of amines with primary function. First, in the reaction vessel contribute 0.05 mmol amine and with the help of a synthesizer type of pipette of 0.038 mmol of sulfochloride in the form of a solution in dichloroethane and 0.05 mmol of triethylamine in solution in dihl is retune. After 24 hours, to the mixture first, 3 ml of saturated sodium bicarbonate solution, and then the reaction mixture was filtered through a double cartouche. After evaporation of the filtrate in vacuo get target audiences.

All reactions are controlled by thin-layer chromatography. When after 24 hours at room temperature does not fully turning, the mixture is heated for an additional 12 hours at 60°and after the reaction finished.

Example 336

Trihydrate hydrochloride 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it.

Free base from example 19 is recrystallized from a mixture of organic solvent and dilute aqueous hydrochloric acid, thereby obtaining hydrochloride trihydrate.

TPL: 218°

Water content: 9,4% (Fisher)

The content of chloride: 6,1%.

Example 337

The dihydrochloride of 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it

0.35 g (0,712 mmol) 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it is suspended in 8 ml of ether and add this amount of dichloromethane, to obtain a homogeneous solution. Then add 2.4 ml of 1 M hydrochloric acid solution in ether, stirred for 20 minutes at room temperature and sucked off. Obtain 372 mg (99%) of the dihydrochloride of 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-it.

200 MHz1H - NMR (DMSO-d6): of 0.96, t, 3H; 1,22, t, 3H; 1,36, t, 3H; 1,82, sex., 2N; 2,61, s, 3H; 2,88, m, 2H; is 3.08, m, 6N; 3,59, d, 2H; 3,50, m, 2H; 3,70, m, 2H; 4.25 in, quart., 2N; of 7.48, d, 1H; 7,95, m, 2H; 11,42, s, 1H; 12,45, s, 1H.

We offer you the medicine may be in the form of any STD is bound drug. As examples the following drugs.

Example

Known methods to prepare tablets of the composition, mg: 500 compound of example 19, 55 microcrystalline cellulose, 72 wet corn starch, 30 transverse cross-linked polyvinylpyrrolidone, 5 of silicon dioxide and 5 stearate.

Example B (pill)

Known methods to prepare tablets of the composition, mg: 100 connection example 16, 20, 26, 27, 32, 260, 275 or 337, 50 lactose monohydrate, 50 corn starch, 10 polyvinylpyrrolidone with a molecular weight of 25 (a product of the company BASF, Germany) and 2 stearate.

The example In (granulate)

25 parts of water is added to a mixture of 10 parts of the compound of example 19, 30 weight. hours of bentonite (montmorillonite), 58 parts of talc and 2 parts of salt ligninsulfonate acid, and the mixture was thoroughly stirred. The resulting mixture granularit using ekstrasensov granulator to obtain granules with a size of 10 to 40 mesh. The resulting granulate is dried at a temperature of from 40 to 50°C.

Example G (granular)

95 parts of clay with a particle size of 0.2 to 2 mm are served in a rotating mixer and uniformly moistened by sprayed a mixture of 5 parts of the compound of example 19 and the liquid diluent. The obtained granules are dried at a temperature of from 40 to 50°C.

Example D (emulsifiable concentrate)

Emulsifiable concentrate is obtained by peremeci the project 30 parts compound of example No. 19, and 5.5 parts of xylene, 8 parts of a simple polyoxyethyleneglycol ether and 7 parts of Las calcium.

Example F (wettable powder)

Wettable powder is obtained by thoroughly mixing 15 parts of the compound of example 19, 80 parts of a mixture powder of hydrated non-crystalline silicon dioxide (trade product of White Carbon) and powder clay in the ratio of 1:5, 2 parts of Las sodium and 3 parts of powder product condensation alkylnaphthalene sodium and formaldehyde.

Example G (wettable granules)

Wettable granules by thoroughly mixing 20 parts of the compound of example 19, 30 parts ligninsulfonate sodium, 15 parts of bentonite and 35 parts of powdered soda diatomeous land with water. The resulting mixture granularit through sieves the size of the holes of 0.3 mm, followed by drying.

1. 2-Phenylseleno imidazolidinone General formula (I)

in which

R1represents a linear alkyl containing up to 4 carbon atoms,

R2represents a linear alkyl containing up to 4 carbon atoms,

R3and R4represent hydrogen or linear or branched alkenyl or alkoxy containing, respectively, up to 4 at the MOU carbon or represent a linear or branched alkyl chain containing up to 6 carbon atoms which may be interrupted by oxygen atom, and may have from one to three same or different of the following substituents: hydroxy, methoxy, carboxyl, linear or branched alkoxycarbonyl containing up to 4 carbon atoms and/or residues of formula-SO3H, -(A)a-NR7R8, -O-CO-NR7'R8',

where

and means the number 0 or 1,

And means balance or SO2,

R7and R8the same or different and mean hydrogen, or mean cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl, and these heterocycles may have from one to two same or different of the following substituents: hydroxy, nitro, carboxyl, fluorine, chlorine, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of the formula -(SO2C)c-NR12R13where means the number 0 or 1, R12and R13the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms, or

R7and R8mean methoxy, or mean a linear or branched alkyl containing up to 6 carbon atoms, which which in some cases has one or two, the same or different substituent: hydroxy, fluorine, chlorine, phenyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula -(CO)d-NR14R15where R14and R15the same or different and mean hydrogen, methyl or ethyl, and d means the number 0 or 1, or

R7and R8together with the nitrogen atom form morpholinyl, piperidinyl or thiazolidine ring or residue of the formula

where

R16means hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinil or N-methylpiperazine, or means a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy,

R7'and R8'linear or branched alkyl with 1-6 carbon atoms, and the alkyl chain radicals R3/R4may be substituted by residues from a group comprising cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl and the remnants of the formula

where

R17means hydrogen, hydroxy, formyl, acetyl, alkoxygroup containing up to 3 carbon atoms, or a linear or branched alkyl with carbon atoms to 3, which may be amesen 1 or 2 identical or different substituents from the group including hydroxyl and linear or branched alkoxy containing up to 3 carbon atoms,

these heterocycles may have from one to three, same or different, substituents: fluorine, chlorine, -SO3H, linear or branched alkyl or alkoxy containing up to 3 carbon atoms, hydroxy and/or a residue of formula-SO2-NR18R19where R18and R19the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms,

or R3and R4represent a group of formula-NR20R21where R20and R21different and denote alkyl containing up to 4 carbon atoms,

or R3or R4represent substituted and the remnants of the formula

or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, hinely, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or remnants of the formula

where

R22is the above for R16value or means formyl or acetyl,

however phenyl or heterocycle radicals R3and R4can have from one to two same or different substituents: fluorine, chlorine,triazolyl, carboxyl, linear or branched acyl or alkoxycarbonyl, respectively, containing up to 4 carbon atoms, nitro and/or a group of the formula-SO3H, -OR23, -(SO2)eNR24R25, -P(O)(OR26)(OR27), where e denotes the number 0 or 1, R23means the rest of the formula

means cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen, or a linear or branched alkyl containing up to 3 carbon atoms, which may have as substituents cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, linear or branched alkoxy or alkoxycarbonyl, respectively, containing up to 3 carbon atoms, benzyloxycarbonyl or phenyl which, in turn, can be substituted one to two times, equal or different substituents: methoxy, hydroxy, fluorine or chlorine, or the specified alkyl which may be substituted by residues of formula-CO-NR28R29or-CO-R30where R28and R29the same or different and mean hydrogen or a linear or branched alkyl containing up to 4 carbon atoms, or R28and R29together with the nitrogen atom form morpholinyl, pyrrolidinyl or piperidinyl ring, and R30means phenyl or substituted, R24and R25the same or different and have the above for the radicals R 18and R19value

R26and R27mean hydrogen, methyl, ethyl and/or phenyl and/or heterocycles of the radicals R3and R4can be substituted linear or branched alkyl containing up to 3 carbon atoms, which may have as substituents hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl and/or a group of formula -(SO2R31, P(O)(OR32)(OR33or-NR34R35where R31means methyl, R32and R33the same or different and have the above for the radicals R26and R27value

R34and R35the same or different and mean hydrogen or a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy or methoxy, or R34and R35together with the nitrogen atom form morpholinyl, thiazolidine or thiomorpholine ring, or a residue of the formula

where

R36means hydrogen, hydroxy, linear or branched alkoxycarbonyl containing up to 3 carbon atoms, or a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by a hydroxy-group, or

R3and R4together with the nitrogen atom form morpholinyl, tio is orgainising, pyrrolidinyl, piperidinyl ring, or a residue of the formula

where

R37means hydrogen, hydroxy, formyl, linear or branched acyl, alkoxy or alkoxycarbonyl, respectively, containing up to 3 carbon atoms, or denotes a linear or branched alkyl containing up to 4 carbon atoms which may have from one to two same or different substituents:

hydroxy, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula (D)fNR38R39, -CO-(CH2)g-O-CO-R40, -CO-(CH2)h-OR41or-P(O)(OR42)(OR43), where g and h are identical or different and denote the number 1, 2, f denotes the number 0 or 1, D denotes a group of the formula-or-SO2, R38and R39the same or different and have the above for the radicals R7and R8value, R40means a linear or branched alkyl containing up to 3 carbon atoms, R denotes a linear or branched alkyl containing up to 3 carbon atoms, R42and R43the same or different and mean hydrogen, methyl or ethyl, or

R37means the residue of formula -(CO)i-E, where i is the number 0 or 1, E means cyclopentyl, benzyl, phenyl, pyridyl, n is Rimadyl or furyl, the ring system can have from one to two same or different substituents: nitro, fluorine, chlorine, -SO3H, linear or branched alkoxy containing up to 3 carbon atoms, hydroxy or a residue of formula-SO2NR44R45where R44and R45the same or different and are indicated for the radicals R18and R19value

or

E. means remains formulas

thus formed together with the nitrogen atom heterocycles mentioned above for the radicals from R3and R4can have from one to three, same or different, may also genialnyh, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula-P(O)(OR46)(OR47),

where R46and R47mean hydrogen, methyl, ethyl,

R48means hydroxy or methoxy,

j means the number 0 or 1, and

R49and R30the same or different and have the above for the radicals R14and R15value

and/or

formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4can be substituted by l nanim or branched alkyl, containing up to 4 carbon atoms which may have from one to three, same or different substituents: hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a residue of formula-SO3H, -NR51R52or-P(O)OR53OR54where R51and R52the same or different and denote hydrogen, phenyl, carboxyl, benzyl or a linear or branched alkyl or alkoxy containing, respectively, to 3 carbon atoms, R53and R54means hydrogen, methyl, ethyl,

or the alkyl may be substituted by phenyl which, in turn, can have from one to two same or different substituents: fluorine, chlorine, hydroxy, methoxy or a group of the formula-NR51′R52′where R51′and R52′the same or different and have the above for the radicals R51and R52value

and/or formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4may have as substituents phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, which can be linked via the N-function, this ring system in turn can be substituted by hydroxy or linear or branched al the sludge or alkoxy, containing up to 3 carbon atoms, or

R3and R4together with the nitrogen atom form the remnants of the formula

thus R3and R4at the same time does not mean hydrogen, and in the case of non-hydrogen values of R3and R4may be the same or different, R5represents hydrogen or a linear alkoxy containing up to 6 carbon atoms,

R6represents a linear alkoxy containing up to 6 carbon atoms, and their salts, hydrates, N-oxides and isomeric forms.

2. 2-Phenylseleno imidazolidinone General formula (I) according to claim 1, in which

R1represents methyl or ethyl, R2represents ethyl or propyl,

R3and R4the same or different and represent linear or branched alkyl chain containing up to 5 carbon atoms which can be substituted one to two times, equal or different way, hydroxy or methoxy,

or

R3and R4together with the nitrogen atom form piperidinyl, morpholinyl, thiomorpholine ring, or a residue of the formula

where

R37means hydrogen, formyl, linear or branched acyl or alkoxycarbonyl, containing the s respectively to 3 carbon atoms, linear or branched alkyl containing up to 3 carbon atoms which may have from one to two same or different, substituents: hydroxy, carboxyl, linear or branched alkoxy or alkoxycarbonyl, respectively, containing up to 3 carbon atoms, or a group of formula(D)fNR38R39or-P(O)(OR42)(OR43), where f denotes the number 0 or 1, D denotes a group of formula-CO, R38and R39the same or different and signify hydrogen or methyl, R42and R43the same or different and mean hydrogen, methyl or ethyl,

or R37means cyclopentyl, thus formed together with the nitrogen atom heterocycles mentioned above for the radicals R3and R4can have from one to two same or different, may also genialnyh, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, to 3 carbon atoms, or a group of formula - P(O)(OR46)(OR47or -(CO)iNR49R50where R46and R47the same or different and mean hydrogen, methyl or ethyl, j means the number 0 or 1, R49and R50the same or different and signify hydrogen or methyl, and/or these heterocycles can be substituted linear or branched alkyl containing up to 3 carbon atoms, to the which may have from one to two, the same or different, substituents: hydroxy, carboxyl or a residue of formula-P(O)(OR53)(OR54), where R53and R54the same or different and mean hydrogen, methyl or ethyl, and/or the heterocycles may contain as a substituent of the N-linked piperidinyl or pyrrolidinyl,

R5represents hydrogen,

R6represents ethoxy or propoxy, and their salts, hydrates, N-oxides and isomeric forms.

3. 2-Phenylseleno imidazolidinone General formula (I) according to claims 1 and 2, selected from the group including

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of hydrochloride,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of the dihydrochloride,

2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one in the form of three-hydrate hydrochloride,

2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-cyclopentylpropionyl-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)phenyl]-5-IU the Il-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

5-methyl-2-(5-morpholine-4-sulfonyl)-2-ethoxyphenyl]-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one,

N,N-diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide,

N-propyl-4-ethoxy-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f] [1,2,4]triazine-2-yl)benzosulfimide.

4. 2-Phenylselenenyl imidazothiazole General formula (I) according to claim 1, which represents a 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one, its salts and hydrates.

5. 2-Phenylselenenyl imidazothiazole General formula (I) according to claim 1, which represents a 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one, hydrochloride and trihydrate hydrochloride.

6. Phenylsilane imidazolidinone General formula (I) according to claim 1, having inhibiting phosphodiesterase I, II and V activity.

7. The method of obtaining 2-phenylselenenyl imidazolidinone according to claim 1, characterized in that the compound of General formula (II)

in which R1and R2have the above meaning,

represents a linear or branched alkyl, containing up to 4 carbon atoms,

subjected to two-stage interaction with the compound of General formula (III)

in which

R5and R6have the above meaning,

in the systems ethanol and phosphorus oxychloride/dichloroethane and the resulting compound of General formula (IV)

in which

R1, R2, R5and R6have the above meaning,

subjected to interaction with chlorosulfonic acid, followed by the interaction of the resulting compounds of General formula (V)

in which

R1, R2, R5and R6have the above meaning,

with an amine of General formula (VI)

in which R3and R4have the above meaning,

in an inert solvent and isolation of the target product.

8. Medicinal product having the properties of an inhibitor of phosphodiesterase I, II and V, containing an active ingredient and a pharmacologically acceptable means, characterized in that the active substance contains compounds of General formula (I) according to claim 1 or their salts, hydrates, N-oxides and isomeric forms.

9. Lech is only the tool of claim 8, characterized in that the active substance contains 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one, its salt or hydrate.

10. The drug of claim 8, wherein the active substance contains 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazine-4-one or its hydrochloride or trihydrate hydrochloride.

Priority signs:

12.11.1997 - have all values of the radicals R1- R6with the exception of values relating to

a) formed by the radicals R3and R4together with the nitrogen atom heterocycles, substituted tetrazolyl,

b) formed by the radicals R7and R8together with the nitrogen atom triazolyl and residues of the formula

in) triazolyl formed by the radicals R34and R35together with the nitrogen atom, which have priority from 31.10.1998, on the filing date of PCT/EP 98/06910.



 

Same patents:

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

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

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition at delayed release contains fluvastatin or its pharmaceutically acceptable salt hydroxypropylmethylcellulose and nonionic hydrophilic polymer. The latter is being hydroxyethylcellulose at average molecular weight ranged 90000-1300000 or hydroxypropylcellulose at average molecular weight ranged 370000-1500000 or polyethylenoxide at average molecular weight ranged 100000-500000. The suggested pharmaceutical composition is necessary to obtain peroral medicinal remedy for decreasing cholesterol level in plasma, it, also, provides the supply of fluvastatin into the body during prolonged period of time, for example, for more than 6 h and enables to minimize the possibility for premature release or "discharge" of considerable fluvastatin quantities.

EFFECT: higher efficiency.

21 cl, 6 dwg, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

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