RU2260593C2 - 2-phenyl-substituted imidazotriazinones, method for their preparing and pharmaceutical composition based on thereof eliciting property of phosphodiesterase i, ii and v inhibitor - Google Patents

Abstract

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-NR^7'R^8',

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; R^7' and R^8' 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

Description

The invention relates to new nitrogen-containing bicyclic compounds with biological activity, in particular to 2-phenyl-substituted imidazotriazinones, a process for their preparation and a medicament based on them having the properties of a phosphodiesterase inhibitor I, II and V.

The patent application DE 28 11 780 describes imidazotriazinones suitable as bronchodilators with antispasmodic activity and inhibitory activity against phosphodiesterases responsible for the metabolism of cyclic adenosine monophosphate (cAMP-PDE, according to Buvo III and PDE nomenclature: PDE . Inhibitory effect on phosphodiesterases responsible for the metabolism of cyclic guanosine monophosphate [cGMP-PDE, according to the nomenclature of Buvo and Raifsnider (Trends in Pharmacol. Sci. 11, 150-155, 1990): PDE-I, PDE-II and PDE- V] not described. No compounds are discussed which contain the sulfonamino group in the aryl residue in the 2nd position. In addition, French patent FR 22 13 058, Swiss patent CH 594 671, German patent applications DE 22 55 172 and 23 64 076 and European patent EP 000 9384 describe imdiso-triazinones which in the 2nd position do not contain any substituted aryl residues , and are also indicated as bronchodilators with cAMP-PDE inhibitory effect (with an inhibitory effect with respect to the cAMP-PDE system).

International application WO 94/28902 describes pyrazolopyrimidinones that are useful in 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 phosphodiesterase inhibitor I, II and V.

The problem is solved by the proposed 2-phenyl-substituted imidazotriazinones of the general formula (I)

wherein

R ¹ is a linear alkyl containing up to 4 carbon atoms, R ² is a linear alkyl containing up to 4 carbon atoms, R ³ and R ⁴ are hydrogen or a 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 an oxygen atom, and may have from one to three, identical or different, of the following substituents: hydroxy, methoxy, carboxyl, linear or azvetvlenny alkoxycarbonyl having up to 4 carbon atoms and / or residues of the formulas -SO ₃ H, - _{(A) a} -NR ⁷ R ^8, -O-CO-NR ^{7 'R 8',}

Where

and means the number 0 or 1,

And means the remainder of CO or SO ₂ ,

R ⁷ and R ^{8 are the} same or different and are hydrogen, or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl, and these heterocycles may have from one to two, the same or different, of the following substituents: hydroxy, nitro, carboxyl, fluorine, chlorine, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or a group of the formula - (SO ₂ C) _c - NR ¹² R ¹³ , where c means the number 0 or 1, R ¹² and R ^{13 are the} same or different and mean hydrogen or linear or branched alkyl containing up to 3 carbon atoms, or

R ⁷ and R ⁸ mean methoxy, or mean linear or branched alkyl containing up to 6 carbon atoms, which in some cases has one or two, identical or different substituents: hydroxy, fluorine, chlorine, phenyl, linear or branched alkoxy or alkoxycarbonyl, containing, respectively, up to 3 carbon atoms, or a group of the formula - (CO) _d —NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are the} same or different and are hydrogen, methyl or ethyl, and d is the number 0 or 1, or

R ⁷ and R ⁸ together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or residues of the formulas

Where

R ¹⁶ means hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or

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

R ⁷ and R ⁸ - linear or branched alkyl with 1-6 carbon atoms, and / or the alkyl chain of R ³ / R ⁴ radicals may be substituted by residues from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl and the remains of the formulas

Where

R ¹⁷ means hydrogen, hydroxy, formyl, acetyl, alkoxy containing up to 3 carbon atoms, or linear or branched alkyl with up to 3 carbon atoms, which may be substituted by 1 or 2 identical or different substituents from the group consisting of hydroxyl and linear or branched alkoxy containing up to 3 carbon atoms,

however, these heterocycles may have from one to three, identical or different, substituents: fluorine, chlorine, —SO ₃ H, linear or branched alkyl or alkoxy containing, respectively, up to 3 carbon atoms, hydroxy and / or a residue of the formula —SO ₂ -NR ¹⁸ R ¹⁹ , where R ¹⁸ and R ^{19 are the} same or different and mean hydrogen or linear or branched alkyl containing up to 3 carbon atoms, or

R ³ and R ⁴ represent a group of the formula —NR ²⁰ R ²¹ where R ²⁰ and R ^{21 are} different and are alkyl containing up to 4 carbon atoms, or

R ³ or R ⁴ are adamantyl, or are residues of the formulas

or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or the radicals of the formulas

Where

R ²² has the meaning given above for R ¹⁶ or means formyl or acetyl,

the phenyl or heterocycles of the radicals R ³ and R ⁴ may have from one to two, identical 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 formulas —SO ₃ H, —OR ²³ , - (SO ₂ ) _e NR ²⁴ R ²⁵ , —P (O) (OR ²⁶ ) (OR ²⁷ ), where e is the number 0 or 1, R ²³ is the remainder of the formula

means cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen, or 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 containing, respectively, up to 3 carbon atoms, benzyloxycarbonyl or phenyl, which, in turn, can be substituted one to two times, with the same or different substituents: methoxy, hydroxy, fluorine or chlorine, or the specified al keel, which may be substituted by residues of the formulas —CO — NR ²⁸ R ²⁹ or —CO — R ³⁰ , where R ²⁸ and R ^{29 are the} same or different and are hydrogen or linear or branched alkyl containing up to 4 carbon atoms, or R ²⁸ and R ²⁹ together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring, and R ³⁰ means phenyl or adamantyl,

R ²⁴ and R ^{25 are the} same or different and have the meaning given above for the radicals R ¹⁸ and R ¹⁹ ,

R ²⁶ and R ²⁷ mean hydrogen, methyl, ethyl,

and / or phenyl and / or heterocycles of the radicals R ³ and R ⁴ may be substituted by linear or branched alkyl containing up to 3 carbon atoms, which may have substituents hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl and / or a group of formulas - (SO ₂ ) R ³¹ , P (O) (OR ³² ) (OR ³³ ) or —NR ³⁴ R ³⁵ , where R ³¹ is methyl, R ³² and R ^{33 are the} same or different and have the above for radicals R ²⁶ and R ²⁷ value,

R ³⁴ and R ^{35 are the} same or different and mean hydrogen or linear or branched alkyl containing up to 3 carbon atoms, which may be substituted by hydroxy or methoxy, or

R ³⁴ and R ³⁵ together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring or a residue of the formula

Where

R ³⁶ means hydrogen, hydroxy, linear or branched alkoxycarbonyl containing up to 3 carbon atoms, or linear or branched alkyl containing up to 3 carbon atoms, which may be substituted by a hydroxy group, or

R ³ and R ⁴ together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring or a residue of the formula

Where

R ³⁷ means hydrogen, hydroxy, formyl, linear or branched acyl, alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or means linear or branched alkyl containing up to 4 carbon atoms, which may have from one to two, identical or various substituents: hydroxy, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or groups of formulas - (D), NR ³⁸ R ³⁹ , -CO- (CH ₂ ) _g -O-CO-R ⁴⁰ , -CO- (CH ₂ ) _h -OR ⁴¹ or -P (O) (OR ⁴² ) (OR ⁴³ ), where g and h are the same or different and mean the number 1, 2, f means the number 0 or 1, D means a group of the formula —CO or —SO ₂ , R ³⁸ and R ^{39 are the} same or different and have the meaning indicated above for the radicals R ⁷ and R ⁸ , R ⁴⁰ means a linear or branched alkyl containing up to 3 carbon atoms, R ⁴¹ means a linear or branched alkyl containing up to 3 carbon atoms, R ⁴² and R ^{43 are the} same or different and mean hydrogen, methyl or ethyl, or

R ³⁷ means the remainder of the formula - (CO) _i -E, where i means the number 0 or 1, E means cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, while these ring systems can have from one to two, the same or different substituents: nitro, fluorine, chlorine, —SO ₃ H, linear or branched alkoxy containing up to 3 carbon atoms, hydroxy or a residue of the formula —SO ₂ —NR ⁴⁴ R ⁴⁵ , where R ⁴⁴ and R ^{45 are the} same or different and are as indicated for radicals R ¹⁸ and R ¹⁹ value, or E means the residues of the formulas

the heterocycles formed together with the nitrogen atom, indicated above for radicals from R ³ and R ⁴ , can have from one to three, identical or different, possibly also heminal, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl, containing, respectively, up to 3 carbon atoms, or groups of formulas -P (O) (OR ⁴⁶ ) (OR ⁴⁷ ),

Where

R ⁴⁶ and R ⁴⁷ mean hydrogen, methyl, ethyl,

R ⁴⁸ means hydroxy or methoxy,

j means the number 0 or 1,

and

R ⁴⁹ and R ^{50 are the} same or different and have the meaning indicated above for the radicals R ¹⁴ and R ¹⁵ , and / or

the heterocycles formed together with the nitrogen atom indicated above for the radicals R ³ and R ⁴ may be substituted by linear or branched alkyl containing up to 4 carbon atoms, which may have from one to three, identical or different substituents: hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or a residue of the formula —SO ₃ H, —NR ⁵¹ R ⁵² or —P (O) OR ⁵³ OR ⁵⁴ , where R ⁵¹ and R ⁵² are identical or different and denote hydrogen, phenyl, carboxyl, benzyl or ineyny or branched alkyl or alkoxy having, respectively, up to 3 carbon atoms, R ⁵³ and R ⁵⁴ is hydrogen, methyl, ethyl, and / or said alkyl may be substituted by phenyl, which in turn can carry one to two identical or different substituents: fluoro, chloro, hydroxy, methoxy or a group of the formula

-NR ^{51 '} R ^52' , where R ^{51 '} and R ^{52' are the} same or different and have the above meaning for the radicals R ⁵¹ and R ⁵² ,

and / or the heterocycles formed together with the nitrogen atom indicated above for the radicals R ³ and R ⁴ may have phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl as substituents, which may also be linked via the N-function, while ring systems, in turn, they can be substituted with hydroxy or linear or branched alkyl or alkoxy containing, respectively, up to 3 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom form residues of the formulas

while R ³ and R ⁴ at the same time do not mean hydrogen, and in the case of non-hydrogen values of R ³ and R ⁴ may be the same or different,

R ⁵ represents hydrogen or linear alkoxy containing up to 6 carbon atoms,

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

The compounds of formula (I) can exist in stereoisomeric forms, which are either either an image and a mirror image (enantiomers) or not like an image and a mirror image (diastereomers). The invention relates both to enantiomers or diastereomers, and to their current mixtures. Racemic forms can also, like diastereomers, be separated in a known manner into stereoisomeric standard constituents.

The compounds of formula (I) may also be in the form of salts. Physiologically safe salts are preferred within the scope of the invention.

Physiologically safe salts may be salts of the claimed compounds with inorganic or organic acids. Salts with inorganic acids, for example, such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids, for example, such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenyl sulfonic acid, toluenesulfonic acid or naphthalene sulfonic acid.

Physiologically safe salts may also be metal salts or ammonium salts of the claimed compounds. Particularly preferred are sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are salts of ammonia or organic amines, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

Preferred are 2-phenyl substituted imidazotriazinones of formula (I) in which

R ¹ represents methyl or ethyl,

R ² represents ethyl or propyl,

R ³ and R ^{4 are the} same or different and represent a linear or branched alkyl chain containing up to 5 carbon atoms, which can be substituted one to two times, in the same or different way, hydroxy or methoxy, or R ³ and R ⁴ together with the atom nitrogen form a piperidinyl, morpholinyl, thiomorpholinyl ring or a residue of the formula

Where

R ³⁷ means hydrogen, formyl, linear or branched acyl or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, linear or branched alkyl containing up to 3 carbon atoms, which may have from one to two, the same or different substituents: hydroxy, carboxyl , linear or branched alkoxy or alkocarbonyl containing, respectively, up to 3 carbon atoms, or groups of formulas - (D) _f NR ³⁸ R ³⁹ or -P (O) (OR ⁴² ) (OR ⁴³ ), where f is the number 0 or 1, D represents a group of the formula -CO, R ³⁸ and R ³⁹ are identical or different and denote in Orod or methyl, R ⁴² and R ⁴³ are identical or different and denote hydrogen, methyl or ethyl, or

R ³⁷ means cyclopentyl,

the heterocycles formed together with the nitrogen atom mentioned above for the radicals R ³ and R ⁴ may have from one to two, identical or different, possibly also heminal, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing , respectively, up to 3 carbon atoms, or a group of formulas —P (O) (OR ⁴⁶ ) (OR ⁴⁷ ) or - (CO) _i NR ⁴⁹ R ⁵⁰ , where R ⁴⁶ and R ^{47 are the} same or different and mean hydrogen, methyl or ethyl, j is the number 0 or 1, and R ⁴⁹ and R ^{50 are the} same or different and are hydrogen or methyl,

and / or said heterocycles may be substituted by linear or branched alkyl containing up to 3 carbon atoms, which may have from one to two, identical or different substituents: hydroxy, carboxyl or a residue of the formula -P (O) (OR ⁵³ ) (OR ⁵⁴⁾ ), where R ⁵³ and R ^{54 are the} same or different and mean hydrogen, methyl or ethyl,

and / or said heterocycles may contain, as substituent, N-linked piperidinyl or pyrrolidinyl,

R ⁵ represents hydrogen,

and

R ⁶ represents ethoxy or propoxy,

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

Particularly preferred are 2-phenyl substituted imidazotriazinones of formula (I) selected from the group consisting of

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

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

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

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

2- [2-ethoxy-5- (4-cyclopentylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he,

2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2 , 4] triazin-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-he

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

2- [2-ethoxy-5- (4-hydroxypiperidin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he,

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

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

2-phenyl-substituted imidazotriazinones of the formula (I) can be obtained due to the fact that the compound of the general formula (II)

wherein

R ¹ and R ² have 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)

wherein

R ⁵ and R ⁶ have the above meaning,

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

wherein

R ¹ , R ² , R ⁵ and R ⁶ have the above meaning, are reacted with chlorosulfonic acid, followed by reaction of the resulting compound of general formula (V)

wherein

R ¹ , R ² , R ⁵ and R ⁶ have the above meaning, with an amine of general formula (VI)

wherein

R ³ and R ⁴ have the above meaning, in an inert solvent and the selection of the target product.

This method, which is an additional object of the invention, is illustrated by the following reaction scheme:

Suitable solvents for the individual steps are conventional organic solvents which do not change under the reaction conditions. These include esrirs, for example, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane , trichloromethane, carbon tetrachloride, dichloroethane, trichlorethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethyltriamide phosphoric acid (hexametapol), acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of these solvents. Ethanol is particularly preferred for the first step, and dichloroethane for the second step.

The reaction temperature, in the General case, can vary in a wide range. In the General case, operate in the range from -20 ° C to 200 ° C, preferably from 0 ° C to 70 ° C.

The indicated process steps are generally carried out at normal pressure. But it is also possible to carry them out under increased or reduced pressure (for example, in the range from 0.5 to 5 bar).

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

The reaction with amines of the general formula (VI) takes place in one of the above chlorinated hydrocarbons, preferably in dichloromethane. Moreover, the reaction temperature, in the General case, can vary in a wide range. In the General case, operate in the range from -20 ° C to 200 ° C, preferably from 0 ° C to room temperature.

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

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

wherein

R ² has the above meaning,

and

T is halogen, preferably chlorine, is first reacted with compounds of general formula (VIII)

wherein

R ¹ has the above meaning,

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

trimethylsilyl chloride and the resulting compounds of General formula (IX)

wherein

R ¹ and R ² have the above meaning, are reacted with a compound of formula (X)

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

Conventional organic solvents which do not change under the reaction conditions are suitable as a solvent for the individual process steps. These include esters, for example, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethyltriamide phosphoric acid (hexametapol), acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of these solvents. Dichloromethane is particularly preferred for the first step, and a mixture of tetrahydrofuran and pyridine for the second step.

Suitable alkali metal hydrides or alkoxides, for example, such as sodium hydride or potassium tert-butylate, or cyclic amines, for example, such as piperidine, pyridine, dimethylaminopyridine or alkylamines, in which alkyl is 1-4 carbon atoms, for example, 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 on, respectively, 1 mole of the compound of formula (X).

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

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

Compounds of general formula (III) can be prepared such that compounds of general formula (XI)

wherein

R ⁵ and R ⁶ have the above meaning,

subjected to interaction with ammonium chloride in toluene and in the presence of triethylaluminum in hexane in the temperature range from -20 ° C to room temperature, preferably at 0 ° C, and normal pressure, and the resulting amidine is reacted, if necessary in situ, with hydrazine hydrate.

Compounds of general formula (XI) are known and can be prepared by conventional methods.

The compounds of general formula (IV) are partially known or are new and then can be obtained 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 prepared from compounds of general formula (IV) based on Organikum publication, VEB Deutscher Verlag der Wissenschaften, Berlin, 1974, Seite 338-339.

The compounds of general formula (I) inhibit either one or more of the metabolism of cGMP phosphodiesterases (PDE I, PDE II and PDE V). This leads to an increase in cGMP level. The differentiated expression of phosphodiesterases in various cells, tissues and organs, as well as the differentiated subcellular localization of this enzyme, makes it possible, in combination with the claimed selective inhibitors, the selective orientation of various processes regulated by cGMP.

In addition, the compounds of general formula (I) enhance the action of substances such as EDRF (relaxing factor produced by endothelium), ANP (atrial sodium-uretic peptide), vasodilators containing nitro groups, and all other substances that in any way as phosphodiesterase inhibitors increase the concentration of cGM.

Therefore, they can be used in drugs for the treatment of cardiovascular diseases, for example, for the treatment of high blood pressure, neuronal hypertension, chronic and non-chronic tonsillitis, peripheral and cardiac vascular diseases, arrhythmias, for the treatment of thromboembolic diseases and ischemia (ischemia), for example , myocardial infarction, stroke, transient and ischemic attacks, tonsillitis pectoris, peripheral circulation disorders, to prevent residual effects in the nasopharynx after a blood clot olysis therapy, skin translaminar plastic surgery, skin translaminar plastic surgery on coronary vessels and their consequences. In addition, they can also play a role in cerebrovascular diseases. The relaxing effect on smooth muscle makes them suitable for the treatment of diseases of the urogenital system, such as prostatic hypertrophy, incontinence, and also, in particular, for the treatment of erectile dysfunction and female sexual dysfunction.

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

Therefore, a further object of the invention is a medicament having the properties of an inhibitor of phosphodiesterases I, II and V, containing, in addition to pharmaceutically acceptable agents, compounds of the above general formula (I) or their salts, hydrates, N-oxides and isomeric forms thereof as an active substance.

The biological activity of the compounds of the above general formula (I) is confirmed by the following experiment.

Phosphodiesterase Activity (PDE)

cGMP-stimulated PDE II, cGMP-inhibited PDE III and cAMP-specific PDE IV were isolated from either the myocardium of pigs or cattle (bulls). Ca ⁺ -calmodulin-stimulated PDE I was isolated from a pig’s aorta, pig’s brain, or preferably from a bull’s aorta. cGMP - specific PDE V was obtained from the small intestine of pigs, pig aorta, human platelets, and preferably from bull aorta. Purification was carried out using anion exchange chromatography on MonoG ^R Pharmacia mainly according to the method of M. Noe and Miles D. Hoslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al., Biochemical Pharmacology, Vol .35, 1743-1751 (1986).

The enzymatic activity was determined in a 100 μl test tube in 20 mM Tris / HCl buffer, pH 7.5, which contained 5 mM magnesium chloride, 0.1 mg / ml albumin from bovine serum and either 800 Bq ³ NcAMP or ³ NcGMP . The final concentration of the corresponding nucleotide was 10 ^-6 mol / L. The reaction started with the addition of the enzyme, the amount of enzyme was calculated in such a way that during the incubation time of 30 minutes, about 50% of the substrate was subjected to conversion. For testing cGMP-stimulated PDE II, ³ NcAMP was used as a substrate and a portion (weighed) of 10 ^-6 mol / L of unlabeled (unlabeled) cGMP was added. To test the Ca ⁺ -calmodulin-dependent PDE I, more calcium chloride in an amount of 1 mM and calmodulin in an amount of 0.1 μM were added to the reaction mixture. The reaction was terminated by the addition of 100 μl of acetonitrile, which contained 1 mM cAMP and 1 mM AMP. 100 μl of the reaction sample was separated using HPLC (liquid chromatography), and the separated products were quantified "Online" on a scintillation counter. The concentration of the substance was measured at which the reaction rate decreased by 50%. In addition, standard test kits for enzyme analysis (activity) were used for testing: Phosphodiesterase [ ³ H] cAMP-SPA enzyme assay and Phosphodiesterase [ ³ H] cGMP-SPA enzyme assay from Amersham Life Science. The test was carried out according to the method specified by the manufacturer. To determine the activity of PDE II, the [ ³ H] cAMP -SPA assay kit was used, with 10 ^-6 M cGMP added to the reaction sample to activate the enzyme. To test PDE I, 10 ^-7 M calmodulin and 1 cM calcium chloride were added to the reaction sample. PDE V testing was performed using the [ ³ H] cGMP-SPA assay kit.

In vitro phosphodiesterase inhibition Test compound of Example No. PDE I IC ₅₀ [nM] PDE II IC ₅₀ [nM] PDEU V IC ₅₀ [nM] 16 300 > 1000 2 19 200 > 1000 2 twenty 200 > 1000 2 26 100 > 1000 1 27 200 > 1000 3 32 100 > 1000 4 260 300 > 1000 10 275 fifty > 1000 3 337 200 > 1000 5

In general, the inhibition of one or more phosphodiesterases of this type leads to an increase in the concentration of cGMP. Thus, the compounds are interesting for many types of therapy in which an increase in cGMP concentration can be considered beneficial.

A study of the effects on the cardiovascular system was conducted on SH rats and dogs. Substances were administered intravenously or orally.

A study of stimulating erection effects was conducted on live rabbits [Naganuma H., Egashira T., Fuji J., Clinical and Experimental Pharmacology and Physiology 20, 177-182 (1993)]. The substances were administered intravenously, orally or parenterally.

New substances, as well as their physiologically safe salts (for example, hydrochlorides, maleates or lactates) can be introduced in a known manner into conventional formulations (forms), such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using an inert, non-toxic, pharmaceutically acceptable carrier or solvent. In this case, the therapeutically active compound should in each case be in a concentration of from about 0.5 to 90% by weight of the total amount of the mixture, i.e. in quantities that are sufficient to achieve the prescribed dosage interval.

The compositions are made, for example, by mixing the active substance with solvents and / or carriers, if necessary using emulsifiers and / or dispersants, while, for example, when using water as a diluent, an organic solvent can be used as an auxiliary solvent.

The introduction of (drugs) is carried out in the usual way, preferably orally, transdermally (on the skin) or parenterally, for example, under the tongue, behind the cheek, intravenously, nasally, rectally or in the form of inhalation.

When used in humans for oral administration, suitable dosages are from 0.001 to 50 mg / kg, preferably 0.01 to 20 mg / kg. For parenteral administration, such as through the nasal mucosa, on the cheek, in the form of inhalation, an appropriate dosage is from 0.001 to 0.5 mg / kg.

Despite this, in some cases, it is required to change the indicated amounts, namely, depending on the body weight or route of administration, on the individual tolerance of the drug, on the type of composition, on the time of administration or the interval through which the drug is taken. So, in some cases, lower doses are sufficient than the aforementioned minimum quantities, while in other cases, the aforementioned upper limit must be exceeded. In the case of the introduction of large quantities, it is recommended to distribute them in several separate doses throughout the day.

The compounds of general formula (I) are also suitable for use in animal medicine (veterinary medicine). For use in animal medicine (veterinary medicine), the compounds or their non-toxic salts in an appropriate composition are administered to animals in accordance with general practice in animal medicine (veterinary medicine). The veterinarian can determine the method of application and dosage in accordance with the type of animal to be treated.

The compounds of general formula (I) are classified as low toxic substances.

The following examples illustrate the preparation of 2-phenyl substituted imidazo-triazinones of the above formula (I).

Source compounds

Example 1A

2-butyrylaminopropionic acid

22.27 g (250 mmol) of 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, 59.75 g (550 ml) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and 1 hour at 40 ° C. After cooling to −10 ° C., 26.64 g (250 mmol) of butyric acid chloride are added dropwise, and the resulting mixture is stirred for 2 hours at −10 ° C. and one hour at room temperature.

Then, 125 ml of water are added dropwise with cooling, and the reaction mixture is stirred for 15 minutes at room temperature. The aqueous layer was evaporated to dryness, the residue was triturated with acetone, and the mother liquor was aspirated. After removal of solvent, the residue was chromatographed. The resulting product was dissolved in 3N sodium hydroxide, and the resulting solution was evaporated to dryness. Concentrated hydrochloric acid was added and evaporated to dryness again. The residue was stirred with acetone, filtered off from the precipitated solid, and the solvent was removed in vacuo. 28.2 g (71%) of a viscous oil are obtained, which crystallizes after a while.

200 MHz ¹ H NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex., 2H; 2.07, t, 2H; 4.20, quint., 1 N; 8.09, d, 1H.

Example 2A

2-Butyrylamino 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. 59.75 g (550 ml) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and 1 hour at 40 ° C. After cooling to −10 ° C., 26.64 g (250 mmol) of butyric acid chloride were added dropwise, and the resulting mixture was stirred for 2 hours at −10 ° C. and one hour at room temperature.

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

29.1 g (67%) of a colorless solid are obtained.

200 MHz ¹ H NMR (DMSO-d6): 0.88, 2t, 6H; 1.51, quart., 2H; 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) of ethyl bromide in 500 ml of acetone are refluxed until the next day. The solid was filtered off, the solvent was removed in vacuo, and the residue was distilled in vacuo. 30.0 g (97%) of a colorless liquid are obtained.

200 MHz ¹ H NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt, 2H.

Example 4A

2-Ethoxybenzamidine - hydrochloride

21.4 g (400 ml) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0 ° C. 200 ml of a 2M solution of trimethylaluminum in hexane are added dropwise and the mixture is stirred at room temperature until the evolution of gas is complete. After adding 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture was stirred until the next day at 80 ° C. in a water bath.

Under ice cooling, the cooled reaction mass 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 solid is suctioned off and washed with an equal volume of methanol. The mother liquor was evaporated, the resulting residue was stirred with a mixture of dichloromethane and methanol (9: 1), the solid was filtered off and the mother liquor was evaporated. 30.4 g (76%) of a colorless solid are obtained.

200 MHz ¹ H NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

Example 5A

2-Propoxybenzonitrile

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 are refluxed until the next day. The solid was filtered off, the solvent was removed in vacuo, and the residue was distilled in vacuo.

Mp: 89 ° C (0.7 mbar)

Yield: 95.1 g (93.7%)

Example 6A

2-Propoxybenzamidine hydrochloride

21.41 g (400 mmol) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5 ° C. Then 200 ml of a solution of a 2M solution of triethylaluminum in hexane are added dropwise, and the mixture is stirred at room temperature until gas evolution is complete. After adding 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture was stirred until the next day at 80 ° C. in a water bath. Under ice-cooling, the cooled reaction mixture was added to a suspension of 300 g of silica gel and 2.85 L of ice-cold chloroform and stirred for 30 minutes. The solid is suctioned off and washed with an equal volume of methanol. The solvent was distilled off in vacuo, the residue was stirred in 500 ml of a mixture of dichloromethane and methanol (9: 1), the solid was filtered off and the mother liquor was evaporated. The residue was triturated with petroleum ether and filtered off with suction. 22.3 g (52%) of the expected product are obtained.

¹ H-NMR (200 MHz, CD ₃ OD): 1.05 (3H); 1.85 (sex, 2H); 4.1 (t, 2H); 7.0-7.2 (m, 2H); 7.5-7.65 (m, 2H).

Example 7A

2-ethoxy-4-methoxybenzonitrile

30.0 g (201 mmol) of 2-hydroxy-4-methoxybesonitrile, 83.4 g (603 mmol) of potassium carbonate and 32.88 g (301 mmol) of bromoethane in 500 ml of acetone are boiled for 18 hours. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (cyclohexane: ethyl acetate = 10: 1). 35.9 g of oil are obtained.

R _f = 0.37 (cyclohexane: ethyl acetate = 3: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.48, t, 3H; 3.85, s, 3H; 4.12, quart., 2H; 6.46, m, 2H; 7.48, d, 1H.

Example 8A

2-Ethoxy-4-methoxybenzamidine - hydrochloride

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

The cooled reaction mass is added with ice cooling 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 solid is suctioned off and washed with an equal volume of methanol. The mother liquor was evaporated, the resulting residue was stirred with a mixture of dichloromethane and methanol (9: 1), the solid was filtered off and the mother liquor was evaporated. The residue was triturated with petroleum ether and filtered off with suction. 7.95 g (50%) of solid are obtained.

200 MHz ¹ H NMR (DMSO-d6): 1.36, t, 3H; 3.84, s, 3H; 4.15, quart., 2H; 6.71, m, 2H; 7.53, d, 1H; 8.91, s, broad, 3H.

Example 9A

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

24.4 g of N-acetyl-D, L-alanine are dissolved in 200 ml of absolute tetrahydrofuran, and 45 ml of absolute pyridine and 0.5 g of dimethylaminopyridine are added, heated to boiling and 51.85 g (0.372 mol) of oxalyl monoethyl ester are added dropwise. acids. The resulting mixture was heated for another 90 minutes at the boil, cooled, poured onto ice water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated and dissolved in 62.5 ml of methanol. 9 g of sodium bicarbonate are added, stirred for 2.5 hours and filtered.

To a solution of 38.26 g (190.65 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in 250 ml of methanol, 9.54 g (190.65 mmol) of hydrazine hydrate are added dropwise while cooling with ice, and the resulting suspension is stirred for another 30 minutes at room temperature . The methanol solution described above was added to the indicated reaction mixture and stirred for 4 hours at a temperature of a water bath of 70 ° C. After filtration, the solution was evaporated, the residue was partitioned between two solvents: dichloromethane and water, the organic layer was dried over sodium sulfate, and the solvent was removed in vacuo.

The residue was dissolved in 250 ml of 1,2-dichloroethane, 32.1 ml (348 mmol) of phosphorus oxychloride was added dropwise, and it was heated under reflux for two hours. The mixture was cooled, evaporated, dissolved in a small amount of methylene chloride, diethyl ether was added and the solid was suctioned off. It is chromatographed on silica gel (methylene chloride / methanol 95: 5), and the crystalline residue is triturated with diethyl ether.

Yield: 8.1 g (14.9% of theory)

200 MHz ¹ H NMR (CDCl ₃ ): 1.58, t, 3H; 2.62, s, 3H; 2.68, s, 3H; 4.25 qq, 2H; 7.04, 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] triazin-4-one

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF, and after adding DMAP at the tip of the spatula, they are heated to boiling. Then, 12.29 g (90 mmol) of oxalic acid monoethyl ester acid chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The resulting mass was poured onto ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on a rotor. The residue was dissolved in 15 ml of ethanol, 2.15 g of sodium bicarbonate was added and boiled for 2.5 hours. The cooled solution is filtered.

2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol under ice-cooling, and the resulting suspension is stirred for another 10 minutes at room temperature. The ethanol solution described above was added to the resulting reaction mixture and stirred for 4 hours at a temperature of a water bath of 70 ° C. After filtration, the solution was evaporated, the residue was partitioned between two solvents: dichloromethane and water, the organic layer was dried over sodium sulfate, and the solvent was removed in vacuo.

The resulting residue was dissolved in 60 ml of 1,2-dichloroethane, and after adding 7.5 ml of phosphorus oxychloride, it was boiled for two hours. The mixture was diluted with dichloromethane and neutralized by adding a solution of sodium bicarbonate and solid sodium bicarbonate. The organic layer was dried and the solvent was removed in vacuo. Chromatography with ethyl acetate and crystallization gave 4.00 g (28%) of a colorless solid,

R _f = 0.42 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex., 2H; 2.67, s, 3H; 3.00, t, 2H; 4.26, quart., 2H; 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] triazin-4-one

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF, and after dimethylaminopyridine is added to the tip of the spatula, it is heated to boiling. Then, 12.29 g (90 mmol) of oxalic acid monoethyl ester acid chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The resulting mass was poured onto ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on a rotor. The residue was dissolved in 15 ml of ethanol, 2.15 g of sodium bicarbonate was added and boiled for 2.5 hours. The cooled solution is filtered.

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

The resulting residue was dissolved in 60 ml of 1,2-dichloroethane, and after adding 7.5 ml of phosphorus oxychloride, it was boiled for two hours. The mixture was diluted with dichloromethane and neutralized by adding a solution of sodium bicarbonate and solid sodium bicarbonate. The organic layer was dried and the solvent was removed in vacuo. Crystallization from ethyl acetate gave 2.85 g (19.1%) of a yellow solid, chromatographic purification of the mother liquor gave another 1.25 g (8.4%) of the target product.

R _f = 0.45 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H-NMR (CDCl ₃ ): 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] triazin-4-one

5.50 g (34.8 mmol) of 2-butyrylaminopropionic acid and 8.19 g of pyridine are dissolved in 35 ml of THF, and after dimethylaminopyridine is added to the tip of the spatula, it is heated to boiling. Then, 9.43 g (69 mmol) of oxalic acid monoethyl ester acid chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The resulting mass was poured onto ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on a rotor. The residue was dissolved in 11 ml of methanol, 1.65 g of sodium hydrogen carbonate was added and boiled for 2.5 hours. The cooled solution is filtered.

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

The resulting residue was dissolved in 46 ml of 1,2-dichloroethane, and after adding 5.74 ml of phosphorus oxychloride, it was boiled for two hours. The mixture was diluted with dichloromethane and neutralized by adding a solution of sodium bicarbonate and solid sodium bicarbonate. The organic layer was dried and the solvent was removed in vacuo. Chromatography (dichloromethane / methanol = 50: 1) gives 0.31 g (2.5%) of solid.

R _f = 0.46 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.03, t, 3H; 1.58, t, 3H; 1.88, m, 2H; 2.62, s, 3H; 2.98, t, 2H; 3.89, s, 3H; 4.25, quart., 2H; 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] triazin-4-one

29.06 g (167.8 mmol) of 2-butyrylaminopropionic acid and 39.67 g of pyridine are dissolved in 170 ml of THF, and after dimethylaminopyridine is added to the tip of the spatula, it is heated to boiling. Then, 45.81 g (335.5 mmol) of oxalic acid monoethyl ester acid chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The resulting mass was poured onto ice water, extracted three times with ethyl acetate, dried over sodium sulfate and evaporated on a rotor. The residue was dissolved in 15 ml of methanol, 7.96 g of sodium bicarbonate was added and boiled for 2.5 hours. The cooled solution is filtered.

To a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzamidine hydrochloride in 85 ml of ethanol, 4.20 g (83.9 mmol) of hydrazine hydrate are added dropwise while cooling with ice, and the resulting suspension is stirred for another 10 minutes at room temperature. The methanol solution described above was added to this reaction mixture and stirred for 4 hours at a temperature of a water bath of 70 ° C. After filtration, the solution was evaporated, the residue was partitioned between two solvents: dichloromethane and water, the organic layer was dried over sodium sulfate, and the solvent was removed in vacuo.

The resulting residue was dissolved in 112 ml of 1,2-dichloroethane, and after adding 14 ml of phosphorus oxychloride, it was boiled for two hours. The mixture was diluted with dichloromethane and neutralized by adding a solution of sodium bicarbonate and solid sodium bicarbonate. The organic layer was dried and the solvent was removed in vacuo. Chromatography (dichloromethane / methanol = 50: 1) gives 3.69 g (12.4%) of a colorless solid.

R _f = 0.46 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.32, t, 3H; 1.57, t, 3H; 1.94, m, 8H; 3.03, quart., 2H; 3.64, quint., 1H; 4.27, quart., 2H; 7.06, d, 1H; 7.12, t, 1H; 7.50, dt, 1H; 8.16, dd, 1H; 9.91, s, 1H.

Example 14A

4-Ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzene sulfochloride

To 7.25 g (25.5 mmol) of 2- (2-ethoxyphenyl) -5-ethyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one while cooling, 26.74 g (0.23 mmol) of chlorosulfonic acid are added. The mixture was stirred at room temperature until the next day, poured onto ice water, the crystals were sucked off and dried in a vacuum desiccator.

Yield 9.5 g (97% of theory)

200 MHz ¹ H-NMR (DMSO-d6): 1.32, t, 3H; 2.63, s, 3H; 2.73, s, 3H; 4.13 q, 2H; 7.15, d, 1H; 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] triazin-2-yl) benzenesulfonyl chloride

2.00 g (6.4 mmol) of 2- (2-ethoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] -triazin-4-one slowly added at 0 ° C to 3.83 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured onto ice water and extracted with dichloromethane. 2.40 g (91%) of a colorless foam are obtained.

200 MHz ¹ H-NMR (CDCl ₃ ): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex., 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 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] triazin-2-yl) benzenesulfonyl chloride

2.80 g (8.6 mmol) of 2- (2-propoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one slowly added at 0 ° C to 5.13 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured onto ice water and extracted with dichloromethane. 3.50 g (96%) of a colorless foam are obtained.

R _f = 0.49 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.03, 2t, 6H; 1.95, m, 4H; 2.81, s, 3H; 3.22, t, 2H; 4.11, t, 2H; 7.09, m, 1 N; 8.06, dd, 1 N; 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] triazin-2-yl) benzenesulfonyl chloride

0.31 g (0.9 mmol) 2- (2-ethoxy-4-methoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine- 4-it is slowly added at 0 ° C to 0.54 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured onto ice water and extracted with dichloromethane. 0.355 g (89%) of a colorless foam is obtained.

R _f = 0.50 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 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., 2H; 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] triazin-2-yl) benzenesulfonyl chloride

1.70 g (5.21 mmol) of 2- (2-ethoxyphenyl) -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] -triazin-4-one slowly added at 0 ° C to 3.12 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature until the next day, poured onto ice water and extracted with dichloromethane. Obtain 2.10 g (94%) of a colorless foam.

200 MHz ¹ H-NMR (CDCl ₃ ): 1.03, t, 3H; 1.35, t, 3H; 1.62, t, 3H; 1.92, sex., 2H; 3.07, quart., 2H; 3.12, t, 2H; 4.42, quart., 2H; 7.38, d, 1H; 8.19, dd, 1H; 8.70, d, 1H; 10.08, s, broad, 1H.

Example 19A

(4-Piperidinylmethyl) phosphonic acid diethyl ester

2.11 g (528 mmol) of a 60% solution of sodium hydride in 50 ml of absolute ethanol are placed in a reaction vessel and 15.7 g (52.8 mmol) of methanediphosphonic acid diethyl ether are added dropwise. It is stirred for 30 minutes at room temperature and then 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone are added dropwise. The resulting mixture was stirred for one hour at room temperature and one hour at the boil, evaporated, treated with water, extracted three times with dichloromethane, dried over sodium sulfate and evaporated. The residue was hydrogenated in 50 ml of ethanol per 1.7 g of 10% palladium on activated carbon at room temperature and a pressure of 3 bar. The catalyst is suctioned off and the filtrate is evaporated.

Yield: 12.5 g (100% of theory)

400 MHz ¹ H NMR (CDCl ₃ ): 1.13, m, 2H; 1.32, t, 6H; 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-furoxanecarbaldehyde

40 g (571 mmol) of crotonic aldehyde are dissolved in 80 ml of acetic acid and a solution of 137 g (1.99 mmol) of sodium nitrite in 300 ml of water is added dropwise at 0 ° C. Stirred for 2 hours at room temperature. Dilute 800 ml of water and extract 3 times with dichloromethane. After drying the organic layer by chromatography (cyclohexane / ethyl acetate), 13.8 g (18.9%) of 5-methyl-4-furoxanecarbaldehyde are obtained.

200 MHz ¹ H NMR (CDCl ₃ ): 2.39, s, 3H; 10.10, s, 1H.

Example 21A

5-methyl-4-furoxanecarboxylic acid chloride

13.5 g (105 mmol) of 5-methyl-4-furoxanecarbaldehyde are dissolved in 200 ml of acetone and a solution of 16.86 g (168 mmol) of chromium trioxide in 120 ml of 2.2 M sulfuric acid is added at 0 ° C. The mixture is stirred for 2 hours at 10-15 ° C and at room temperature until the next day. Then, with cooling, 100 ml of isopropanol are added dropwise, and after 30 minutes the solvent is removed in vacuo. The aqueous layer was extracted 3 times with ether, the organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in a 1 M sodium hydroxide solution, and the solution was extracted 3 times with ether. The aqueous layer was acidified and extracted 3 times with ether. The organic layer was dried and the solvent was removed in vacuo. The residue is stirred (triturated) with petroleum ether and filtered off with suction.

6.92 g of the residue and 10 ml of thionyl chloride in 20 ml of dichloromethane are refluxed for 6 hours. Dilute with toluene, filter and evaporate on a rotor. The residue was redissolved in dichloromethane, 10 ml of thionyl chloride were added and boiled for 48 hours. The solvent was removed in vacuo and the residue was distilled in vacuo.

2.00 g (25%) of colorless crystals are obtained.

200 MHz ¹ H NMR (CDCl ₃ ): 2.41, s.

Example 22A

1- (5-Methyl-4-furoxanecarbonyl) -4-tert-butyl-hydroxycarbonyl-piperazine

2.75 g (14.7 mmol) of Boc-piperazine and 1.49 g of triethylamine are dissolved in 20 ml of dichloromethane and 2.00 g (12.3 mmol) of 5-methyl-4-furoxanecarboxylic acid chloride are added in portions at 0 ° C. acids. The mixture was stirred for 30 minutes at 0 ° C and 2 hours at room temperature, diluted with dichloromethane and washed with water. The solvent was removed in vacuo and the residue was purified by chromatography (cyclohexane / ethyl acetate). 3.33 g (87%) of 1- (5-methyl-4-furoxanecarbonyl) -4-tert-butyl-hydroxycarbonyl-piperazine are obtained.

200 MHz ¹ H NMR (CDCl ₃ ): 1.50, s, 9H; 2.30, s, 3H; 3.55, m, 4H; 3.78, m, 2H 3.87, m, 2H.

Example 23A

1- (5-Methyl-4-furoxanecarbonyl) piperazine trifluoroacetate

3.12 g (10 mmol) of 1- (5-methyl-4-furoxanecarbonyl) -4-tert-butyl-hydroxycarbonyl-piperazine was dissolved in 20 ml of dichloromethane, and 2 ml of trifluoroacetic acid was added at 0 ° C. The mixture was allowed to spontaneously warm to room temperature and stirred for 72 hours. After adding 10 ml of ether, the precipitate is suctioned off and dried. 2.47 g (83%) of 1- (5-methyl-4-furoxanecarbonyl) piperazine trifluoroacetate are obtained.

200 MHz ¹ H 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, s, broad, 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] triazin-4-one

0.1 g (0.26 mmol) 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2 -yl) benzenesulfonyl chloride is dissolved in 10 ml of dichloromethane and cooled to 0 ° C. After adding DMAP (dimethylaminopyridine) at the tip of a spatula, 80 mg (0.784 mmol) of N-methylpiperazine was added and the reaction mixture was stirred at room temperature until the next day. It is diluted with dichloromethane, the organic layer is washed with a solution of ammonium chloride, dried over sodium sulfate and the solvent is removed in vacuo. The residue was chromatographed 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-hydroxyethylpiperazin-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 100 mg (0.784 mmol) of 4-hydroxyethylpiperazine give 45 mg (36.1% of theory) of 2- [2-ethoxy-5- (4-hydroxyethylpiperazin-1-sulfonyl) phenyl] -5.7 dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

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

Example 3

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

Similarly, based on 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) benzenesulfonyl chloride and 80 mg (0.784 mmol) of 4-hydroxypiperidine give 35 mg (29.8% of theory) of 2- [2-ethoxy-5- (4-hydroxypiperidin-1-sulfonyl) phenyl] -5 , 7-dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

200 MHz ¹ H-NMR (CDCl ₃ )): 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 qt; 2H; 7.18, d, 1H; 7.90, dd, 1H; 8.52, d, 1H; 9.73, s, 1H.

Example 4

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 90 mg (4,484 mmol) of 4-hydroxymethylpiperidine, 22 mg (18% of theory) of 2- [2-ethoxy-5- (4-hydroxymethylpiperidin-1-sulfonyl) phenyl] -5,7-dimethyl -3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 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 q, 2H; 7.21, d, 1H; 7.95, dd, 1H; 8.51, d, 1H; 10.03, br.s, 1H.

Example 5

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) -benzenesulfonyl chloride and 70 mg (0.784 mmol) of 3-hydroxypyrrolidine give 13 mg (11.1% of theory) of 2- [2-ethoxy-5- (3-hydroxypyrrolidin-1-sulfonyl) phenyl] -5, 7-dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

Mass spectrum: 434 (M + H)

Example 6

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) -benzenesulfonyl chloride and 70 mg (0.784 mmol) of 2- (ethylamino) ethanol, 23 mg (20.1% of theory) of 4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5 , 7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.2, t, 3H; 1.6, t, 3H; 2.17, broad s, 1H; 2.69, s, 3H; 2.75, s, 3H; 3.33, m, 4H; 3.8, t, 2H; 4.36 qt; 2H; 7.18, d, 1H; 7.99, dd, 1H; 8.6, d, 1H; 9.84, broad s, 1H.

Example 7

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzene sulfochloride and 60 mg (0.784 mmol) of diethylamine, 21 mg (18.6% of theory) of N, N-diethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3) are obtained , 4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzene sulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.18, t, 6H; 1.61, t, 3H; 2.68, s, 3H; 2.72, s, 3H; 3.29 qt; 4H; 4.35 q, 2H; 7.15, d, 1H; 7.95, dd, 1H; 8.58, d, 1H; 9.8 br.s, 1H.

Example 8

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 130 mg (0.784 mmol) of 1- (2-pyrimidinyl) piperazine, 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] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 1.6, t, 3H; 2.68, s, 3H; 2.72, s, 3H; 3.12, t, 4H; 3.96, t, 4H; 4.34 q, 2H; 6.5, t, 1H; 7.18, d, 1H; 7.9, dd, 1H; 8.28, d, 2H, 8.51, d, 1H; 9.7, broad s, 1H;

Example 9

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 70 mg (0.784 mmol) of morpholine give 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] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 1.53, t, 3H; 2.69, s, 3H; 2.72, s, 3H; 3.06, t, 4H; 3.77, t, 4H; 4.39 q, 2H; 7.2, d, 1H; 7.91, dd, 1H; 8.51, d, 1H; 9.78, broad s, 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] triazin-4-one

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 100 mg (1,484 dioxol-1,4-azaspiro [4.4] nonane) give 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] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 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 q, 2H; 7.17, d, 1H; 7.92, dd, 1H; 8.51, d, 1H; 9.92, broad s, 1H.

Example 11

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) benzenesulfamide

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 100 mg (0.784 mmol) of bis (2-ethoxyethyl) amine, 37 mg (27.5% of theory) of N, N-bis (2-methoxyethyl) -4-ethoxy-3- are obtained (5, 7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.58, t, 3H; 2.61, s, 3H; 2.64, s, 3H; 3.3, s, 6H; 3.46, t, 4H; 3.56, t, 4H; 4.32 q, 2H; 7.12, d, 1H; 7.95, dd, 1H; 8.51, d, 1H; 9.9, broad s, 1H.

Example 12

N- (3-Isoxazole yl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2- silt) benzenesulfamide

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 70 mg (0.784 mmol) of 3-aminoisoxazole give 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] triazin-2-yl) benzenesulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.6, t, 3H; 2.73, s, 3H; 2.81, s, 3H; 4.35 q., 2H; 6.6, d, 1H; 7.14, d, 1H; 8.05, dd, 1H; 8.27, d, 1H; 8.63, d, 1H; 9.61, broad s, 1H.

Example 13

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 170 mg (0.784 mmol) of 2-tert-butoxycarbonylaminomethylmorpholine receive 64 mg (22.2% of theory) of 2- [2-ethoxy-5- (2-tert-butoxycarbonylaminomethylmorpholine-4-sulfonyl) phenyl] - 5,7-dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

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] triazin-4-one

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 130 mg (0.784 mmol) of 1-phenylpiperazine give 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] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 1.62, t, 3H; 2.72, s, 3H; 2.77, s, 3H; 3.25, m, 8H; 4.38 qt; 2H; 6.92, m, 2H; 7.02, d, 1H; 7.18-37, m, 3H; 7.94, dd, 1H; 8.55, m, 1H; 9.79, broad s, 1H.

Example 15

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

Similarly, based on 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride and 100 mg (0.784 mmol) of 3-hydroxy-3-methoxymethylpyrrolidine, 30 mg (23.5% of theory) of 2- [2-ethoxy-5- (3-hydroxy-3-methoxymethylpyrrolidin-1- sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

Mass spectrum: 478 (M + H)

Example 16

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

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

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex., 2H; 2.29, s, 3H; 2.51, m, 4H; 2.63, s, 3H; 3.00, t, 2H; 3.08, m, 4H; 4.33 qq, 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] triazin-4 -on 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] triazin-4-one is suspended in 5 ml of ether and 20 mg of an 85% solution of lactic acid in water are added. Stirred for 10 minutes at room temperature and evaporated to dryness. Triturated with ether and suctioned off. Obtain 110 mg (92%) of lactate 2- [2-ethoxy-5- (4-methylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1 , 2,4] triazin-4-one.

200 MHz ¹ H NMR (DMSO-d6): 0.92, t, 3H; 1.22, d, 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., 2H; 7.40, d, 1H; 7.85, m, 2H; 11.71, broad s, 1H.

Example 18

2- [2-Ethoxy-5- (4-methylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -on 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] triazin-4-one is suspended in 5 ml of diethyl ether, 0.23 ml of a 1 M solution of hydrochloric acid in ether are added and stirred for 15 minutes at room temperature. The solvent is removed in vacuo. Obtain 110 mg (97%) of 2- [2-ethoxy-5- (4-methylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] - [1] hydrochloride , 2,4] -triazin-4-one.

200 MHz ¹ H-NMR (DMSO-d ₆ ): 0.93, t, 3H; 1.35, t, 3H; 1.75, sex., 2H; 2.72, s, 3H; 2.86, m, 4H; 3.15, m, 2H; 3.45, m, 2H; 3.81, m, 2H; 4.25, quart., 2H; 7.45, d, 1H; 7.95, m, 2H; 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] triazin-4 -he

470 mg (1.14 mmol) 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2 -yl) benzenesulfonyl chloride is dissolved in 20 ml of dichloromethane and cooled to 0 ° C. 390 mg (3.42 mmol) of N-ethylpiperazine was added and the reaction mixture was stirred at room temperature until the next day. It is diluted with dichloromethane, the organic layer is washed twice with water, dried over sodium sulfate and the solvent is removed in vacuo. Crystallization from ether gives 370 mg (66%) of a colorless solid.

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex., 2H; 2.42, quart., 2H; 2.56, m, 4H; 2.63, s, 3H; 3.00, t, 2H; 3.10, m, 4H; 4.33, quart., 2H; 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] triazin-4 -on 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] triazin-4-one is suspended in 5 ml of ether and dichloromethane is added so that the solution becomes homogeneous. Then add 0.8 ml of a 1 M solution of hydrochloric acid in ether, stirred for 20 minutes at room temperature and suctioned off. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] hydrochloride is obtained [1, 2,4] triazin-4-one.

200 MHz ¹ H-NMR (DMSO-d ₆ ): 0.96, t, 3H; 1.22, t, 3H; 1.36, t, 3H; 1.82, sex., 2H; 2.61, s, 3H; 2.88, m, 2H; 3.08, m, 6H; 3.50, m, 2H; 3.70, m, 2H; 4.25, quart., 2H; 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-aminopiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4 ] triazin-4-one

Similarly, based on 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) benzene sufochloride and 0.03 g (0.29 mmol) of 1-amino-4-methylpiperazine, 40 mg (83%) of 2- [2-ethoxy-5- (4-methyl-1) are obtained -amino-piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.09 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.59, t, 3H; 1.90, sex., 2H; 2.22, s, 3H; 2.40, 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-aminopiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4 ] triazin-4-one

Similarly, based on 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) benzene sulfonyl chloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine, 46 mg (91%) of 2- [2-ethoxy-5- (4-hydroxyethyl-1) are obtained -amino-piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.08 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.59, t, 3H; 1.90, sex, 2H; 2.49, m, 6H; 2.62, s, 3H; 2.71, m, 4H; 3.00, t, 2H; 3.55, t, 2H; 4.31, quart., 2H; 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) benzenesulfamide

Similarly, based on 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) benzenesulfonyl chloride and 0.043 g (0.29 mmol) of N, N-bis (hydroxyethyl) aminoethylamine give 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] triazin-2-yl) benzenesulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.53, t, 3H; 1.70, m, 2H; 1.86, sex., 2H; 2.9, m, 9H; 2.95, t, 2H; 3.09, t, 2H; 3.65, t, 4H; 4.28, quart., 2H; 7.14, d, 1H; 7.95, dd, 1H; 8.35, d, 1H.

Example 24

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

Similarly, starting from 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] triazin-2-yl) -benzenesulfonyl chloride, 390 mg triethylamine and 0.86 g (2.99 mmol) 4-dimethoxyphosphorylmethyl piperazine, 321 mg (53%) of 2- [2-ethoxy-5- (4) -dimethoxyphosphorylmethyl-piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] -triazin-4-one.

R _f = 0.4 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.60, t, 3H; 1.88, sex., 2H; 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., 2H; 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-diethoxyphosphorylmethyl-piperidin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazine -4-he

Similarly, starting from 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] triazin-2-yl) -benzenesulfonyl chloride and 0.86 g (3.7 mmol) of 4-diethoxyphosphoryl-methyl-piperidine, 366 mg (49%) of 2- [2-ethoxy-5- (4-diethoxyphosphorylmethyl) are obtained -piperidin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.4 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H-NMR (DMSO-d ₆ ): 0.92, t, 3H; 1.20, t, 6H; 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., 2H; 7.38, d, 1H; 7.87, m, 2H; 11.70, s, 1H.

Example 26

2- [2-Ethoxy-5- (4-hydroxypiperidin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he

Similarly, starting from 531 mg (1.29 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 393 mg (3.88 mmol) of 4-hydroxypiperidine, 400 mg (64% of theory) of 2- [2-ethoxy-5- (4-hydroxypiperidin-1-sulfonyl) phenyl are obtained ] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz ¹ H 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., 2H; 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) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2 , 4] triazin-4-one

Similarly, starting from 411 mg (1 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 391 mg (3 mmol) of 1-hydroxyethylpiperazine give 380 mg (75% of theory) of 2- [2-ethoxy-5- (4- (2-hydroxyethyl) -piperazin-1-sulfonyl ) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.198 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.60, m, 7H; 3.00, t, 2H; 3.10, m, 4H; 3.60, t, 2H; 4.36, quartet, 2H; 7.18, d, 1H; 7.89, dd, 1H; 8.47, d, 1H; 9.71, s, 1H.

Example 28

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

200 mg (0.39 mmol) 2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1 -f] - [1,2,4] triazin-4-one is suspended in ether, 2 ml of 1M hydrochloric acid in ether are added and stirred for 20 minutes at room temperature. Removal of the solvent gave 209 mg (100%) of 2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo hydrochloride [ 5.1-f] [1,2,4] triazin-4-one.

200 MHz ¹ H NMR (DMSO-d6): 0.96, t, 3H; 1.35, t, 3H; 1.70, sex., 2H; 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., 2H; 7.49, d, 1H; 7.95, m, 2H; 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] triazin-4-one

Similarly, based on 150 mg (0.37 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 158 mg (1.09 mmol) of 4- (3-hydroxypropyl) piperazine give 167 mg (83% of theory) of 2- [2-ethoxy-5- (4- (3 -hydroxypropyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.52 (dichloromethane / methanol = 10: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.70, m, 5H; 2.62, m, 8H; 3.00, t, 2H; 3.10, m, 4H; 3.72, t, 2H; 4.36 quart., 2H; 7.18, d, 1H; 7.89, dd, 1H; 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 ] triazin-2-yl) benzenesulfamide

Similarly, based on 420 mg (1.02 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) benzenesulfonyl chloride and 300 mg (3 mmol) allyl (hydroxyethyl) amine, 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] triazin-2-yl) benzenesulfamide.

R _f = 0.345 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.90, m, 2H; 2.22, broad s, 1H; 2.62, s, 3H; 2.99, t, 2H; 3.31, t, 2H; 3.78, t, 2H; 3.92, d, 2H; 4.37, quart., 2H; 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 ] triazin-2-yl) benzenesulfamide

Similarly, starting from 411 mg (1.0 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfonyl chloride and 267 mg (3 mmol) ethyl (hydroxyethyl) amine, 325 mg (70% of theory) of N-ethyl-N- (2-hydroxyethyl) -4-ethoxy-3- ( 5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) benzenesulfamide.

R _f = 0.29 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.20, t, 3H; 1.61, t, 3H; 1.88, sex., 2H; 2.30, broad s, 1H; 2.62, s, 3H; 2.99, t, 2H; 3.32, m, 4H; 3.78, t, 2H; 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] triazin-2-yl ) benzenesulfamide

Similarly, based on 400 mg (0.97 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 210 mg (2.92 mmol) of diethylamine give 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] triazin-2-yl) benzenesulfamide.

R _f = 0.49 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.20, t, 6H; 1.49, t, 3H; 1.61, t, 3H; 1.88, sex., 2H; 2.30, broad s, 1H; 2.62, s, 3H; 2.99, t, 2H; 3.32, m, 4H; 3.78, t, 2H; 3.80, m, 2H; 4.37, quart., 2H; 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) benzenesulfamide

Similarly, starting from 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfonyl chloride and 680 mg (9 mmol) of (2-methoxyethyl) amine, 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] triazin-2-yl) benzenesulfamide.

R _f = 0.25 (dichloromethane / methanol = 95: 5)

400 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.58, t, 3H; 1.88, sex., 2H; 2.62, s, 3H; 3.01, t, 2H; 3.18, quart., 2H; 3.30, s, 3H; 3.45, t, 2H; 4.32, quart., 2H; 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 ] triazin-2-yl) benzenesulfamide

Similarly, based on 210 mg (0.49 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 130 mg (9 mmol) of 2-N, N-dimethylethylamine, give 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] triazin-2-yl) benzene sulfamide.

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.62, m, 4H; 1.88, sex., 2H; 2.11, s, 6H; 2.39, t, 2H; 2.63, s, 3H; 3.01, m, 3H; 4.38, quart., 2H; 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] triazin-2-yl) benzenesulfamide

Similarly, starting from 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 1.3 g (9 mmol) of 3- (1-morpholino) propylamine, 1.38 g (88%) of N- [3- (1-morpholino) propyl] -4 is obtained -ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) benzene sulfamide.

R _f = 0.23 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.58, t, 3H; 1.72, m, 2H; 1.88, sex., 2H; 2.46, s, 6H; 2.62, s, 3H; 3.01, t, 2H; 3.15, t, 2H; 3.71, t, 4H; 4.32, quart., 2H; 7.13, d, 1H; 7.97, dd, 1H; 8.53, d, 1H; 9.79, s, 1H.

Example 36

N- [3- (4-Methylpiperazino) propyl] -4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-digi-droimidazo [5,1-f] - [1, 2,4] triazin-2-yl) benzenesulfamide

Similarly, based on 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 0.05 g (0.29 mmol) of 3- [4-methylpiperazino] propylamine give 0.04 g (77%) of N- [3- (4-methylpiperazino) propyl] -4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) benzenesulfamide.

R _f = 0.11 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.55, t, 3H; 1.68, m, 2H; 1.88, sex., 2H; 2.27, s, 3H; 2.45, s, 8H; 2.62, s, 3H; 2.98, m, 3H; 3.10, t, 2H; 3.46, s, 1H; 4.30, quart., 2H; 7.13, d, 1H; 7.97, dd, 1H; 8.53, d, 1H.

Example 37

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

Similarly, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) -benzenesulfonyl chloride and 40 mg (0.29 mmol) of 4- (methoxyethyl) piperazine, 50 mg (99% of theory) of 2- [2-ethoxy-5- (4- (2-methoxyethyl) - piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.27 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 2H; 2.60, m, 9H; 2.97, t, 2H; 3.10, m, 4H; 3.46, t, 2H; 3.60, s, 3H; 4.36, quart., 2H; 7.18, d, 1H; 7.89, dd, 1H; 8.47, d, 1H; 9.71, s, 1H.

Example 38

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

Similarly, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 50 mg (0.29 mmol) of 4- (2-N, N-dimethylaminoethyl) piperazine give 50 mg (99%) of 2- [2-ethoxy-5- (4- (2 -N, N-dimethylaminoethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.11 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.20, s, 6H; 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; 8.47, d, 1H, 9.71, s, 1H.

Example 39

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

Similarly, based on 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 130 mg (0.73 mmol) 4- (3-N, N-dimethylaminopropyl) piperazine, 72 mg (54%) of 2- [2-ethoxy-5- (4- (2) -N, N-dimethylaminoethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.08 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, sex., 3H; 2.20, s, 6H; 2.25, m, 2H; 2.38, t, 2H; 2.52, m, 4H; 2.63, s, 3H; 2.99, m, 6H; 4.33, quart., 2H; 7.18, d, 1H; 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 40

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

Similarly, based on 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 100 mg (0.73 mmol) of 4-dioxolanopiperidine give 111 mg (88%) of 2- [2-ethoxy-5- (4- (dioxolanopiperidin-1-sulfonyl) phenyl] -5- methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.80, m, 6H; 2.63, s, 3H; 2.99, t, 2H; 3.20, m, 4H; 3.90, s 4H; 4.33, quart., 2H; 7.18, d, 1H; 7.89, dd, 1H, 8.47, d, 1H; 9.71, s, 1H.

Example 41

2- [2-Ethoxy-5- (4- (5-methyl-4-furoxanecarbonyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1 , 2,4] triazin-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] triazin-2 -yl) benzenesulfonyl chloride is dissolved in 10 ml of dichloromethane and cooled to 0 ° C. 590 mg (2.00 mmol) of 1- (5-methyl-4-furoxanecarbonyl) piperazine and 400 mg of triethylamine are added, and the reaction mixture is stirred at room temperature until the next day. It is diluted with dichloromethane, the organic 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 vacuo. Crystallization from ether gives 448 mg (74%) of a colorless solid.

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex, 2H; 2.25, s, 3H; 2.63, s, 3H; 3.00, t, 2H; 3.20, m, 4H; 3.90, m, 2H; 4.02, m, 2H; 4.33 quart., 2H; 7.19, d, 1H; 7.89, dd, 1H; 8.48, d, 1H; 9.57, s, 1H.

Example 42

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

Similarly, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 40 mg (0.29 mmol) of N-acetylpiperazine give 9 mg (18% of theory) of 2- [2-ethoxy-5- (4-acetylpiperazin-1-sulfonyl) phenyl] - 5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.34 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, sex., 3H; 2.05 s, 3H; 2.63, s, 3H; 3.00, m, 6H; 3.59, m, 2H; 3.72, m, 2H; 4.33, quart., 2H; 7.18, d, 1H; 7.89, dd, 1H; 8.47, d, 1H; 9.71, s, 1H.

Example 43

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

Similarly, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 30 mg (0.29 mmol) of N-formylpiperazine give 35 mg (73% of theory) of 2- [2-ethoxy-5- (4-formylpiperazin-1-sulfonyl) phenyl] - 5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.29 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.87, sex., 3H; 2.05 s, 3H; 2.63, s, 3H; 3.00, m, 6H; 3, 50, m, 2H; 3.69, m, 2H; 4.33, quart., 2H; 7.18, d, 1H; 7.89, dd, 1H; 8.00, s, 1H; 8.47, d, 1H; 9.71, s, 1H.

Example 44

2- [2-Ethoxy-5- (3-butylsidnonimine) sulfonylphenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one

110 mg (0.6 mmol) of 3-butylsidononimine hydrochloride is dissolved in 2.5 ml of pyridine and cooled to 0 ° C. 210 mg (0.5 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-f] [1,2,4] triazin-2 are added -yl) benzenesulfonyl chloride, and the reaction mixture was stirred for 2 hours at 0 ° C, and then at room temperature until the next day. Dilute with dichloromethane, wash the organic layer with water, dry over sodium sulfate, and remove the solvent in vacuo. Chromatography (dichloromethane / methanol) affords 16 mg (6%) of 2- [2-ethoxy-5- (3-butylsidonimonine) sulfonylphenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] triazin-4-one.

R _f = 0.41 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, 2t, 6H; 1.47, sex., 2H; 1.55, t, 3H; 1.88, m, 2H; 2.04 quint. 2H; 2.62, s, 3H; 2.98, t, 2H; 4.29, quart., 2H; 4.41, t, 2H; 7.08, d, 1H; 7.56 s, 1H; 7.98, dd, 1H; 8.58, d, 1H; 9.79, broad s, 1H.

Example 45

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

0.85 g (2 mmol) 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2- il) benzenesulfonyl chloride is dissolved in 20 ml of dichloromethane and cooled to 0 ° C. After adding DMAP at the tip of a spatula, 0.60 g (6.00 mmol) of N-methylpiperazine was added and the reaction mixture was stirred at room temperature until the next day. It is diluted with dichloromethane, the organic layer is washed with a solution of ammonium chloride, dried over sodium sulfate and the solvent is removed in vacuo. Crystallization from ether gives 0.80 g (77%) of a colorless solid.

R _f = 0.233 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.00, t, 3H; 1.15, t, 3H; 1.87, hex., 2H; 1.99, hex., 2H; 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-hydrochloride

22 mg (0.045 mmol) 5-methyl-2- [5- (4-methylpiperazin-1-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5,1-f] - [1, 2,4] triazin-4-one is dissolved in 2 ml of ether and 1 ml of dichloromethane and 0.1 ml of a 1 M solution of hydrochloric acid in ether is added. After 20 minutes, the precipitate formed is suctioned off and dried.

200 MHz ¹ H NMR (CDCl ₃ ): 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-Hydroxypiperidin-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazine- 4-he

Similarly, starting from 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) -benzenesulfonyl chloride and 610 mg (6 mmol) of 4-hydroxypiperidine give 736 mg (75% of theory) of 2- [5- (4-hydroxypiperidin-1-sulfonyl) -2-propoxy-phenyl] -5 methyl 7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one

R _f = 0.07 (dichloromethane / methanol = 95: 5)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.16, t, 3H; 1.80, m, 9H; 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-Hydroxymethylpiperidin-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4 -he

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfonyl chloride and 35 mg (0.3 mmol) of 4-hydroxymethylpiperidine, 41 mg (82% of theory) of 2- [5- (4-hydroxymethylpiperidin-1-sulfonyl) -2-propoxy- phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one

R _f = 0.52 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 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) piperazin-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2 , 4] triazin-4-one

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 39 mg (3 mmol) of 4-hydroxyethylpiperazine, give 50 mg (96% of theory) of 2- [5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) -2 -propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.43 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.88, m, 2H; 2.00, m, 2H; 2.62, m, 9H; 3.00, t, 2H; 3.07, m, 4H; 3.58, t, 2H; 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-dioxotetrahydro-1λ ^6- thiophen-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2 , 4] triazin-2-yl) -4-propoxy-benzenesulfamide

Similarly, based on 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 41 mg (3 mmol) of 2-aminosulfolane give 8 mg (14% of theory) of N- (1,1-dioxotetrahydro-1λ ^6- thiophen-3-yl) 3- ( 5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.49 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 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, 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] triazin-2 -yl) -4-propoxybenzenesulfamide

Similarly, based on 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 31 mg (0.3 mmol) 1,1,4-trimethyldiaminoethane, 39 mg (79% of theory) of N- (2-dimethylaminoethyl) -N-methyl-3- ( 5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f | - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.28 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.88, m, 2H; 2.01, m, 2H; 2.25, s, 6H; 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; 7.91, dd, 1H; 8.50, d, 1H; 9.70, s, 1H.

Example 52

N- (3-Morpholin-4-yl-propyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 43 mg (0.3 mmol) of 1- (3-aminopropyl) morpholine, 52 mg (97% of theory) of N- (3-morpholin-4-ylpropyl) -3- are obtained (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.33 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.71, m, 2H; 1.93, m, 4H; 2.43, m, 6H; 2.62 s, 3H; 2.98, t, 2H; 3.12, t, 2H; 3.70, m, 4H; 4.21, t, 2H; 7.15, d, 1H; 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- sludge) -4-propoxy-benzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 32 mg (0.3 mmol) of bis (hydroxyethyl) amine, 34 mg (69% of theory) of N, N-bis (2-hydroxyethyl) -3- (5-methyl) are obtained -4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.36 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 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] triazin-2-yl) - 4-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 37 mg (0.3 mmol) of 3-hydroxybenzylamine, 4 mg (8% of theory) of N- (3-hydroxybenzyl) -3- (5-methyl-4-oxo- 7-propyl-3,4-dihydroimidazo [5.1-1] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.43 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 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; 5.05, t, 1H; 6.52 s, 1H; 6.70, m, 2H; 7.06, m, 2H; 7.93, dd, 1H; 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-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 27 mg (0.3 mmol) ethyl (hydroxyethyl) amine, 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] triazin-2-yl) -4-propoxybenzene sulfamide.

R _f = 0.48 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.15.2 t, 6H; 1.75, s, 2H; 1.85, m, 2H; 1.98, m, 2H; 2.40, s, 1H; 2.62, s, 3H; 2.99, t, 2H; 3.32, m, 4H; 3.90, quart., 2H; 4.21, quart., 2H; 7.15, d, 1H; 7.95, dd, 1H; 8.55, d, 1H; 9.73, s, 1H.

Example 56

N- (3-Ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) - 4-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 31 mg (0.3 mmol) of (3-ethoxypropyl) amine, 47 mg (96%) of N- (3-ethoxypropyl) -3- (5-methyl-4-oxo) are obtained -7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.60 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, m, 6H; 1.89, m, 7H; 2.62, s, 3H; 3.00, t, 2H; 3.12, quart., 2H; 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-Hydroxypiperidin-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazine- 4-he

Similarly, starting from 212 mg (0.5 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 152 mg (1.5 mmol) of 4-hydroxypiperidine, 125 mg (50% of theory) of 2- [5- (4-hydroxypiperidin-1-sulfonyl) -2-propoxy- phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.07 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 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] triazin-2-yl) -4-propoxy-N- (pyridin- 4-yl) -benzenesulfamide

Similarly, starting from 85 mg (0.2 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 56 mg (0.6 mmol) of 4-aminopyridine, after 18 hours refluxing in 1 ml of tetrahydrofuran, 24 mg (25% of theory) of 3- (5-methyl- 4-oxo-7-propyl-3,4-dihydroimidazo [5.1-1] - [1,2,4] triazin-2-yl) -4-propoxy-N- (pyridin-4-yl) benzene sulfamide .

R _f = 0.13 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 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; 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] triazin-2-yl) -4-propoxy -benzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 22 mg (0.6 mmol) of diethylamine, 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] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.64 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.18, 2t, 9H; 1.92, 2hex., 4H; 2.62, s, 3H; 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] triazin-2-yl) -4-propoxy-benzenesulfonyl ] -piperidin-4-carboxylic acid

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 14 mg (0.6 mmol) of piperidinecarboxylic acid in 1 ml of a mixture of THF and water (1: 1) with 26.5 mg of sodium carbonate, get 21 mg (41%) 1- [3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonyl] - piperidine-4-carboxylic acid

R _f = 0.28 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.90, t, 3H; 1.04, t, 3H; 1.80, m, 4H; 2.21, m, 2H; 2.51, s, 3H; 2.85, m, 2H; 3.56, m, 6H; 4.10, t, 2H; 7.12, d, 1H; 7.71, dd, 1H; 8.10, d, 1H; 10.72, broad s, 1H.

Example 61

5-Methyl-2- [5- (morpholin-4-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4- he

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 26 mg (0.3 mmol) of morpholine, 34 mg (71%) of 5-methyl 2- [5- (morpholin-4-sulfonyl) -2-propoxy-phenyl] - 7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.64 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.16, t, 3H; 1.89, hex., 2H; 2.00, hex., 2H; 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-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 23 mg (0.63 mmol) methyl (hydroxyethyl) amine, 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] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.53 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.82, m, 2H; 1.99, hex., 2H; 2.40, broad s, 1H; 2.62, s, 3H; 2.89, s, 3H; 2.99, t, 2H; 3.21, t, 2H; 3.80, broad s, 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-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5.1-1] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 31 mg (0.6 mmol) propyl (hydroxyethyl) amine give 20 mg (40%) N- (2-hydroxyethyl) -N-propyl-3- (5-methyl-4 -oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.52 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.90, t, 3H; 1.01, t, 3H; 1.15, t, 3H; 1.52, m, 2H; 1.88, m, 2H; 2.00, m, 2H; 2.40, s, 1H; 2.63, s, 3H; 3.01, t, 2H; 3.22, m, 4H; 3.80, quart., 2H; 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-Dimethoxyphenyl) ethyl)] - N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1 , 2,4] triazin-2-yl) -4-propoxy-benzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzene sulfochloride and 59 mg (0.3 mmol) of N-methyl- (3,4-dimethoxyphenyl) ethylamine, 45 mg (78%) of N- [2- (3,4-dimethoxyphenyl) are obtained ) ethyl)] - N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfamide.

R _f = 0.35 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.90, t, 3H; 1.07, t, 3H; 1.78, m, 2H; 1.92, m, 2H; 2.55, s, 3H; 2.73, s, 3H; 2.78, m, 2H; 2.89, t, 2H; 3.23, t, 2H; 3.80, s, 6H; 4.15, t, 2H; 6.65, m, 3H; 7.05, d, 1H; 7.75, dd, 1H; 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-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 31 mg (0.3 mmol) allyl (hydroxyethyl) amine, 34 mg (70%) of N-allyl-N- (2-hydroxyethyl) -3- (5-methyl- 4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.52 (dichloromethane / methanol = 9: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.85, m, 2H; 1.99, m, 2H; 2.38, broad s, 1H; 2.63, s, 3H; 3.00, t, 2H; 3.32, t, 2H; 3.86, t, 2H; 3.90, d, 2H; 4.25, t, 2H; 5.21, m, 2H; 5.71, m, 1H; 7.15, d, 1H; 7.95, dd, 1H; 8.55, d, 1H; 9.77, s, 1H.

Example 66

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

Similarly, based on 42 mg (0.1 mmol of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzene sulfonyl chloride and 38 mg (0.3 mmol) allyl (cyclopentyl) amine, 33 mg (64%) of N-allyl-N-cyclopentyl-3- (5-methyl-4-oxo-7- propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.43 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 3H; 1.53, m, 9H; 2.00, m, 4H; 2.63, s, 3H; 3.00, t, 2H; 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] -triazin-2-yl) -4-propoxybenzenesulfamide

Similarly, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) benzenesulfonyl chloride and 26 mg (0.3 mmol) allyl (ethyl) amine, 30 mg (64%) of N-allyl-N-ethyl-3- (5-methyl-4-oxo-7) are obtained -propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxybenzenesulfamide.

R _f = 0.44 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.15, t, 6H; 1.89, m, 2H; 2.01, m, 2H; 2.63, s, 3H; 3.00, t, 2H; 3.27, quart., 2H; 3.87, d, 2H; 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 ] triazin-4-one

20 mg (0.045 mmol) 4-ethoxy-2-methoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine- 2-yl) -benzenesulfonyl chloride was dissolved in 0.5 ml of dichloromethane, dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine were added on the tip of the spatula, and the reaction mixture was stirred until the next day at room temperature. After purification on siliagel, 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] triazin-4-one.

R _f = 0.22 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.94, t, 3H; 1.55, t, 3H; 1.80, m, 2H; 2.24, s, 3H; 2.42, t, 4H; 2.55, s, 3H; 2.92, t, 2H; 3.19, t, 4H; 3.91, s, 3H; 4.25, quart., 2H; 6.48, s, 1H; 8.57 s, 1H; 9.54, s, 1H.

Example 69

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

Similarly, based on 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] triazin-2-yl) -benzenesulfonyl chloride and 18 mg (0.14 mmol) of 4-hydroxyethylpiperazine, 11 mg (46%) of 2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin- 1-sulfonyl) -4-methoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.34 (dichloromethane / methanol = 15: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.94, t, 3H; 1.55, t, 3H; 1.80, m, 3H; 2.52, m, 9H; 2.92, t, 2H; 3.20, t, 4H; 3.44, t, 2H; 3.92, s, 3H; 4.25, quart., 2H; 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] triazin-2-yl) benzene sulfamide

Similarly, based on 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] triazin-2-yl) -benzenesulfonyl chloride and 12 mg (0.14 mmol) ethyl (hydroxyethyl) amine, 8 mg (34%) of 4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -2 are obtained -methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) benzene sulfamide.

R _f = 0.45 (dichloromethane / methanol = 15: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.02, t, 3H; 1.18, t, 3H; 1.61, t, 2H; 1.88, m, 2H; 2.39, broad s, 1H; 2.65, s, 3H; 3.00, t, 2H; 3.38, quart., 2H; 3.45, t, 2H; 3.78, m, 2H; 4.01, s, 3H; 4.20, quart., 2H; 6.58, s, 1H; 8.67, s, 1H; 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 ] triazin-2-yl) benzene sulfamide

Similarly, based on 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] triazin-2-yl) -benzenesulfonyl chloride and 19 mg (0.14 mmol) of 4-ethoxyaniline, 7 mg (34%) of 4-ethoxy-N- (4-ethoxyphenyl) -2-methoxy-5- ( 5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) benzene sulfamide.

R _f = 0.36 (dichloromethane / methanol = 20: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.02, t, 3H; 1.33, t, 3H; 1.59, t, 3H; 1.86. hex., 2H; 2.62, s, 3H; 3.02, t, 2H; 3.92, quart., 2H; 4.11, s, 3H; 4.31, quart., 2H; 6.58, s, 1H; 6.72, d, 2H; 6.88, broad s, 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 ] triazin-2-yl) benzene sulfamide

0.64 g (1.5 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine- 2-yl) benzenesulfonyl chloride is dissolved in 20 ml of dichloromethane and cooled to 0 ° C. After dimethylaminopyridine was added at the tip of a spatula, 0.40 g (4.50 mmol) of 2- (ethylamino) ethanol was added and the reaction mixture was stirred at room temperature until the next day. Dilute with dichloromethane, wash the organic layer with water, dry over sodium sulfate, and remove the solvent in vacuo. Chromatography (dichloromethane / methanol = 95: 5) gives 0.454 g (63%) of a colorless solid.

200 MHz ¹ H-NMR (CDCl ₃ ): 1.02, t, 3H; 1.20, t, 3H; 1.35, t, 3H; 1.61, t, 3H; 1.88, sex., 2H; 2.25, broad s, 1H; 3.01, m, 4H; 3.32, m, 4H; 3.70, m, 2H; 3.80, m, 2H; 4.37, quart., 2H; 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] triazin-2-yl) -4-ethoxy-benzenesulfamide

Similarly, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 21 mg (0.282 mmol) of 2-methoxyethylamine give 15 mg (34%) of N- (2-methoxyethyl) -3- (5-methyl-4-oxo-7-propyl-3, 4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfamide.

R _f = 0.2 (ethyl acetate / cyclohexane = 2: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.97, t, 3H; 1.25, t, 3H; 1.53, t, 3H; 1.82, sex., 2H; 2.97, m, 4H; 3.11, m, 2H; 3.22 s, 3H; 3.39, t, 2H; 4.37, quart., 2H; 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] triazin-2 -yl) -4-ethoxybenzenesulfamide

Similarly, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 38 mg (0.28 mmol) of bis (methoxyethyl) amine, 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] triazin-2-yl) -4-ethoxybenzenesulfamide.

R _f = 0.34 (ethyl acetate / cyclohexane = 2: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.97, t, 3H; 1.27, t, 3H; 1.53, t, 3H; 1.80, sex., 2H; 2.95, m, 4H; 3.22 s, 6H; 3.39, m, 4H; 3.49, m, 4H; 4.27, quart., 2H; 7.17, d, 1H; 7.97, dd, 1H; 8.53, d, 1H; 9.82, s, 1H.

Example 75

2- [5- (4-Hydroxypiperidin-1-sulfonyl) -2-ethoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4- he

Similarly, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-methyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 460 mg (4.5 mmol) of 4-hydroxypiperidine give 485 mg (66%) of 2- [5- (4-hydroxypiperidin-1-sulfonyl) -2-ethoxyphenyl] -5 methyl 7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.37 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.02, t, 3H; 1.32, t, 3H; 1.60, t, 3H; 1.80, m, 7H; 2.97, m, 6H; 3.30, m, 2H; 3.82, m, 1H; 4.34, quart., 2H; 7.17, d, 1H; 7.90, dd, 1H; 8.45, d, 1H; 9.75, s, 1H.

Example 76

2- [5- (4-Hydroxymethylpiperidin-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4 -he

Similarly, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 33 mg (0.28 mmol) of 4-hydroxymethylpiperidine give 23 mg (48%) of 2- [5- (4-hydroxymethylpiperidin-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl -7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 0.38 (dichloromethane / methanol = 10: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 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., 2H; 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) piperazin-1-sulfonyl) phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] - [1,2 , 4] triazin-4-one

Similarly, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -benzenesulfonyl chloride and 37 mg (0.28 mmol) of 4-hydroxyethylpiperazine give 35 mg (71%) of 2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one.

R _f = 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-he

Similarly, starting from 640 mg (1.50 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 450 mg (4.5 mmol) of 4-methylpiperazine give 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] triazin-4-one.

R _f = 0.30 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.35, t, 3H; 1.61, t, 3H; 1.89, sex., 2H; 2.31, s, 3H; 2.53, m, 4H; 3.05, m, 8H; 4.35, quart., 2H; 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-hydrochloride

300 mg (0.61 mmol) 2- [2-ethoxy-5- (4-methylpiperazin-1-sulfonyl) phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] - [ 1,2,4] triazin-4-one is dissolved in a mixture of ether and dichloromethane and 2 ml of a 1 M solution of hydrochloric acid in ether are added. After 20 minutes, the precipitate formed is suctioned off and dried.

200 MHz ¹ H-NMR (DMSO-d ₆ ): 0.95, t, 3H; 1.32, 2t, 6H; 1.80, sex., 2H; 2.76, m, 4H; 3.01, m, 4H; 3.15, m, 2H; 3.44, m, 2H; 3.81, m, 2H; 4.25, quart., 2H; 7.49, d, 1H; 7.95, m, 2H; 11.25, s, 1H; 12.30, s, 1H.

Example 80

N- (3-Morpholin-4-yl-propyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfamide

Similarly, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 650 mg (4.5 mmol) of 1- (3-aminopropyl) morpholine give 476 mg (59%) of 3- (5-ethyl-4-oxo-7-propyl-3 , 4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl) -N- (3-morpholin-4-yl-propyl) -4-ethoxybenzenesulfamide.

R _f = 0.18 (dichloromethane / methanol = 19: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 1.01, t, 3H; 1.32, t, 3H; 1.60, t, 3H; 1.70, m, 3H; 1.89, sex., 2H; 2.43, m, 7H; 3.01, m, 4H; 3.15, t, 2H; 3.70, m, 4H; 4.35, quart., 2H; 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-ethoxybenzenesulfamide

Similarly, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-7-propyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonyl chloride and 464 mg (4.5 mmol) of propyl (hydroxyethyl) amine, 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] triazin-2-yl) -4-ethoxybenzenesulfamide.

R _f = 0.73 (dichloromethane / methanol = 10: 1)

200 MHz ¹ H-NMR (CDCl ₃ ): 0.91, t, 3H; 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; 3.80, m, 2H; 4.35, t, 2H; 7.15, d, 2H; 7.95, dd, 1H; 8.55, d, 1H; 9.75, s, 1H.

The sulfonamides shown in the following tables 1,2,3,4 and 6 were obtained using automated parallel synthesis from 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5 , 1-f) [1,2,4] triazin-2-yl) -benzenesulfonyl chloride and the corresponding amine according to one of the following three standard methods.

The sulfonamides shown in Table 5 were obtained in a similar manner using automated parallel synthesis from 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-δ] [1 , 2,4] triazin-2-yl) -benzenesulfonyl chloride and the corresponding amine.

The purity of the final product was determined using HPLC (high performance liquid chromatography), their characteristics were obtained by measuring the parameters of liquid chromatography and mass spectrum. The content of the target substance according to HPLC-MS (mass spectrum) is indicated in the tables in the column "HPLC" in percent. Standard procedure A was applied in the case of amines with an acid function, standard method B was used in the case of amines with a neutral function, standard method C was used in the case of amines with an additional basic function.

In some cases, the hydrogen atoms are not depicted in the structural formulas shown in tables 1, 2, 3, 4, 5, and 6. Therefore, nitrogen atoms with free valency should be considered as the NH residue.

Standard Procedure A: Reaction of amines with an acid function. First, 0.05 mmol of amine, 0.042 mmol of sulfonyl chloride and 0.10 mmol of sodium carbonate are mixed, and 0.5 ml of a mixture consisting of THF / water are manually added with a pipette. After the mixture was kept at room temperature for 24 hours, 0.5 ml of a 1 M sulfuric acid solution was added and filtered (passed) through a two-phase (two-layer) cartridge (500 mg Extrelut (upper phase) and 500 mg silica, eluent ethyl acetate). After evaporation of the filtrate in vacuo, the target product is obtained.

Standard Procedure B: Reaction of amines with a neutral function. First, 0.125 mmol of amine is introduced into the reaction vessel and 0.03 mmol of sulfonyl chloride is added from a pipette using a synthesizer in the form of a solution in dichloroethane. After 24 hours, 0.5 ml of 1 M sulfuric acid was added to the mixture and filtered through a two-phase (two-layer) cartridge (500 mg Extrelut (upper phase) and 500 mg silica, eluent ethyl acetate). The filtrate was evaporated in vacuo.

Standard Procedure C: Reaction of amines with basic function. First, 0.05 mmol of amine is introduced into the reaction vessel and 0.038 mmol of sulfonyl chloride in the form of a solution in dichloroethane and 0.05 mmol of triethylamine in the form of a solution in dichloroethane are added from a pipette using a synthesizer. After 24 hours, 3 ml of saturated sodium bicarbonate solution was first added to the mixture, and then the reaction mixture was filtered through a double cartridge. After evaporation of the filtrate in vacuo, the target product is obtained.

All reactions are controlled by thin layer chromatography. In the case when complete conversion does not occur after 24 hours at room temperature, the mixture is heated for an additional 12 hours at 60 ° C, and then the reaction is completed.

Example 336

2- [2-Ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] [1,2,4] triazine hydrochloride trihydrate 4-she.

The free base of Example 19 is recrystallized from a mixture of an organic solvent and dilute aqueous hydrochloric acid, and thus the hydrochloride trihydrate is obtained.

Mp: 218 ° C

Water Content: 9.4% (Fisher)

Chloride content: 6.1%.

Example 337

2- [2-Ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] - [1,2,4] triazine dihydrochloride 4-she

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] triazin-4-one is suspended in 8 ml of ether and a quantity of dichloromethane is added so that a homogeneous solution is obtained. Then add 2.4 ml of a 1 M solution of hydrochloric acid in ether, stirred for 20 minutes at room temperature and suctioned off. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] - [1] dihydrochloride is obtained , 2,4] triazin-4-one.

200 MHz ¹ H-NMR (DMSO-d ₆ ): 0.96, t, 3H; 1.22, t, 3H; 1.36, t, 3H; 1.82, sex., 2H; 2.61, s, 3H; 2.88, m, 2H; 3.08, m, 6H; 3.59, d, 2H; 3.50, m, 2H; 3.70, m, 2H; 4.25, quart., 2H; 7.48, d, 1H; 7.95, m, 2H; 11.42, s, 1H; 12.45, s, 1H.

The proposed drug may be in the form of any standard preparation. The following preparations are given as examples.

Example A

By known methods, tablets of the composition, mg: 500, of the compound of Example 19, 55 microcrystalline cellulose, 72 wet corn starch, 30 cross-linked polyvinylpyrrolidone, 5 silicon dioxide and 5 magnesium stearate, are prepared.

Example B (tablet)

By known methods, tablets of the composition are prepared, mg: 100 compounds of Example 16, 20, 26, 27, 32, 260, 275 or 337, 50 lactose monohydrate, 50 corn starch, 10 polyvinylpyrrolidone with a molar weight of 25 (product of BASF, Germany) and 2 magnesium stearate.

Example B (granulate)

25 parts by weight water is added to the mixture 10 parts by weight the compounds of example 19, 30 weight. including concrete (montmorillonite), 58 parts by weight talcum powder and 2 parts by weight salts of ligninsulfonic acid, and the mixture is thoroughly mixed. The resulting mixture was granulated using an extruded granulator to obtain granules with a size of 10 to 40 mesh. The obtained granulate is dried at a temperature of from 40 to 50 ° C.

Example D (granulate)

95 parts by weight clay with a particle size distribution from 0.2 to 2 mm is fed into a rotary mixer and it is evenly moistened by spraying a mixture of 5 parts by weight the compounds of example 19 and a liquid diluent. The obtained granules are dried at a temperature of from 40 to 50 ° C.

Example D (emulsifiable concentrate)

An emulsifiable concentrate is obtained by mixing 30 parts by weight the compounds of example No. 19, 5.5 parts by weight xylene, 8 parts by weight polyoxyethylene alkyl phenyl ether and 7 parts by weight calcium alkylbenzenesulfonate.

Example E (wettable powder)

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

Example G (wettable granulate)

Wettable granules by thoroughly mixing 20 parts by weight the compounds of example 19, 30 parts by weight sodium ligninsulfonate, 15 parts by weight concrete and 35 parts by weight powder calcined diatomaceous earth with water. The resulting mixture was granulated through sieves with a hole size of 0.3 mm, followed by drying.

Claims (11)

1. 2-Phenyl-substituted imidazotriazinones of the general formula (I)

wherein R ¹ represents a linear alkyl containing up to 4 carbon atoms, R ² is a linear alkyl containing up to 4 carbon atoms, R ³ and R ⁴ are hydrogen or linear or branched alkenyl or alkoxy containing, respectively, up to 4 carbon atoms, or are a linear or branched alkyl chain containing up to 6 carbon atoms, which may be interrupted by an oxygen atom, and may have from one to three, identical or different, of the following substituents: hydroxy, methoxy, carboxyl, linear or branched alkoxycarbonyl containing up to 4 carbon atoms, and / or residues of the formulas —SO ₃ H, - (A) _a —NR ⁷ R ⁸ , - O-CO-NR ^{7 '} R ^8' ,

Where and means the number 0 or 1, And means the remainder of CO or SO ₂ , R ⁷ and R ^{8 are the} same or different and are hydrogen, or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl, and these heterocycles may have one to two, the same or different, of the following substituents: hydroxy, nitro, carboxyl, fluorine, chlorine, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or a group of the formula - (SO ₂ C) _c —NR ¹² R ¹³ where c is the number 0 or 1, R ¹² and R ^{13 are the} same or different and mean hydrogen or linear or branched alkyl containing minutes to 3 carbon atoms, or R ⁷ and R ⁸ mean methoxy, or mean linear or branched alkyl containing up to 6 carbon atoms, which in some cases has one or two, identical or different, substituents: hydroxy, fluorine, chlorine, phenyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or a group of the formula - (CO) _d —NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are the} same or different and are hydrogen, methyl or ethyl, and d is the number 0 or 1, or R ⁷ and R ⁸ together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or residues of the formulas

Where R ¹⁶ means hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or means a linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy, R ^{7 '} and R ^{8' is} linear or branched alkyl with 1-6 carbon atoms, wherein the alkyl chain of R ³ / R ⁴ radicals may be substituted by residues from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl and residues formulas

Where R ¹⁷ means hydrogen, hydroxy, formyl, acetyl, alkoxy containing up to 3 carbon atoms, or linear or branched alkyl with up to 3 carbon atoms, which may be substituted by 1 or 2 identical or different substituents from the group consisting of hydroxyl and linear or branched alkoxy containing up to 3 carbon atoms, however, these heterocycles may have from one to three, identical or different, substituents: fluorine, chlorine, —SO ₃ H, linear or branched alkyl or alkoxy containing respectively up to 3 carbon atoms, hydroxy and / or a residue of the formula —SO ₂ - NR ¹⁸ R ¹⁹ , where R ¹⁸ and R ^{19 are the} same or different and mean hydrogen or linear or branched alkyl containing up to 3 carbon atoms, or R ³ and R ⁴ represent a group of the formula —NR ²⁰ R ²¹ where R ²⁰ and R ^{21 are} different and are alkyl containing up to 4 carbon atoms, or R ³ or R ⁴ are adamantyl and residues of the formulas

or are cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or the radicals of the formulas

Where R ²² has the meaning given above for R ¹⁶ or means formyl or acetyl, the phenyl or heterocycles of the radicals R ³ and R ⁴ may have from one to two, the same or different substituents: fluorine, chlorine, triazolyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing respectively up to 4 carbon atoms, nitro and / or group of the formula —SO ₃ H, —OR ²³ , - (SO ₂ ) _e NR ²⁴ R ²⁵ , —P (O) (OR ²⁶ ) (OR ²⁷ ), where e is the number 0 or 1, R ²³ is the remainder of the formula

means cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen, or 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 containing respectively up to 3 carbon atoms , benzyloxycarbonyl or phenyl, which, in turn, can be substituted one to two times, with the same or different substituents: methoxy, hydroxy, fluorine or chlorine, or the indicated alkyl Which can be substituted by radicals of the formulas -CO-NR ²⁸ R ²⁹ or -CO-R ³⁰ where R ²⁸ and R ²⁹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or R ²⁸ and R ²⁹ together with a nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring, and R ³⁰ means phenyl or adamantyl, R ²⁴ and R ^{25 are the} same or different and have the meaning indicated above for the radicals R ¹⁸ and R ¹⁹ , R ²⁶ and R ²⁷ mean hydrogen, methyl, ethyl, and / or phenyl and / or heterocycles of the radicals R ³ and R ⁴ may be substituted by linear or branched alkyl containing up to 3 carbon atoms, which may have hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl and / or a group of formulas - (SO ₂ ) R ³¹ , P (O) (OR ³² ) (OR ³³ ) or —NR ³⁴ R ³⁵ , where R ³¹ means methyl, R ³² and R ^{33 are the} same or different and have the above meaning for the radicals R ²⁶ and R ²⁷ , R ³⁴ and R ^{35 are the} same or different and mean hydrogen or linear or branched alkyl containing up to 3 carbon atoms which may be substituted by hydroxy or methoxy, or R ³⁴ and R ³⁵ together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring or residue formulas

Where R ³⁶ means hydrogen, hydroxy, linear or branched alkoxycarbonyl containing up to 3 carbon atoms, or linear or branched alkyl containing up to 3 carbon atoms, which may be substituted by a hydroxy group, or R ³ and R ⁴ together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring or a residue of the formula

Where R ³⁷ means hydrogen, hydroxy, formyl, linear or branched acyl, alkoxy or alkoxycarbonyl containing respectively up to 3 carbon atoms, or means linear or branched alkyl containing up to 4 carbon atoms, which may have from one to two identical or different substituents: hydroxy, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or groups of formulas - (D) _f NR ³⁸ R ³⁹ , —CO- (CH ₂ ) _g —O — CO — R ⁴⁰ , —CO— (CH ₂ ) _h —OR ⁴¹ or —P (O) (OR ⁴² ) (OR ⁴³ ), where g and h are the same or different and mean the number 1, 2, f means the number 0 or 1, D means a group of the formula —CO or —SO ₂ , R ³⁸ and R ^{39 are the} same or different and have the meaning given above for the radicals R ⁷ and R ⁸ , R ⁴⁰ means a linear or branched alkyl containing up to 3 carbon atoms, R means a linear or branched alkyl containing up to 3 carbon atoms, R ⁴² and R ^{43 are the} same or different and mean hydrogen, methyl or ethyl, or R ³⁷ means the remainder of the formula - (CO) _i -E, where i means the number 0 or 1, E means cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, while these ring systems can have from one to two, the same or different substituents: nitro, fluorine, chlorine, —SO ₃ H, linear or branched alkoxy containing up to 3 carbon atoms, hydroxy or a residue of the formula —SO ₂ NR ⁴⁴ R ⁴⁵ , where R ⁴⁴ and R ^{45 are the} same or different and have the indicated radicals R ¹⁸ and R ¹⁹ value, or E means the remains of the formulas

the heterocycles formed together with the nitrogen atom, indicated above for radicals from R ³ and R ⁴ , can have from one to three, identical or different, possibly also heminal, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl, containing, respectively, up to 3 carbon atoms, or groups of formulas -P (O) (OR ⁴⁶ ) (OR ⁴⁷ ),

where R ⁴⁶ and R ⁴⁷ mean hydrogen, methyl, ethyl, R ⁴⁸ means hydroxy or methoxy, j means the number 0 or 1, and R ⁴⁹ and R ^{30 are the} same or different and have the meaning indicated above for the radicals R ¹⁴ and R ¹⁵ , and / or the heterocycles formed together with the nitrogen atom indicated above for the radicals R ³ and R ⁴ may be substituted by linear or branched alkyl containing up to 4 carbon atoms, which may have from one to three, identical or different substituents: hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, linear or branched alkoxy or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or a residue of the formula —SO ₃ H, —NR ⁵¹ R ⁵² or —P (O) OR ⁵³ OR ⁵⁴ , where R ⁵¹ and R ⁵² are identical or different and denote hydrogen, phenyl, carboxyl, benzyl or ineyny or branched alkyl or alkoxy having, respectively, up to 3 carbon atoms, R ⁵³ and R ⁵⁴ is hydrogen, methyl, ethyl, or said alkyl may be substituted with phenyl, which, in turn, may have from one to two, same or different substituents: fluoro, chloro, hydroxy, methoxy or a group of the formula —NR ^{51 ′} R ^{52 ′} , where R ^{51 ′} and R ^{52 ′ are the} same or different and have the above meaning for the radicals R ⁵¹ and R ⁵² , and / or the heterocycles formed together with the nitrogen atom indicated above for the radicals R ³ and R ⁴ can have phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl as substituents, which can also be linked via the N-function, while ring systems, in turn, can be substituted by hydroxy or linear or branched alkyl or alkoxy containing respectively up to 3 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom form residues of the formulas

wherein R ³ and R ⁴ do not simultaneously mean hydrogen, and in the case of values other than hydrogen, R ³ and R ⁴ may be the same or different, R ⁵ is hydrogen or a linear alkoxy containing up to 6 carbon atoms, R ⁶ is a linear alkoxy containing up to 6 carbon atoms, and their salts, hydrates, N-oxides and isomeric forms thereof. 2. 2-Phenyl-substituted imidazotriazinones of the general formula (I) according to claim 1, in which R ¹ represents methyl or ethyl, R ² represents ethyl or propyl, R ³ and R ^{4 are the} same or different and represent a linear or branched alkyl chain containing up to 5 carbon atoms, which may be substituted one to two times, in the same or different way, hydroxy or methoxy, or R ³ and R ⁴ together with the nitrogen atom form a piperidinyl, morpholinyl, thiomorpholinyl ring or a residue of the formula

Where R ³⁷ means hydrogen, formyl, linear or branched acyl or alkoxycarbonyl containing respectively up to 3 carbon atoms, linear or branched alkyl containing up to 3 carbon atoms, which may have from one to two, identical or different, substituents: hydroxy, carboxyl, linear or branched alkoxy or alkoxycarbonyl containing up to 3 carbon atoms, respectively, or a group of formulas - (D) _f NR ³⁸ R ³⁹ or -P (O) (OR ⁴² ) (OR ⁴³ ), where f means the number 0 or 1, D means a group of the formula —CO, R ³⁸ and R ^{39 are the} same or different and mean carbon or methyl, R ⁴² and R ^{43 are the} same or different and are hydrogen, methyl or ethyl, or R ³⁷ means cyclopentyl, while the heterocycles formed together with the nitrogen atom indicated above for the radicals R ³ and R ⁴ can have from one to two, identical or different, possibly also geminal, substituents: hydroxy, formyl, carboxyl, linear or branched acyl or alkoxycarbonyl containing, respectively, up to 3 carbon atoms, or groups of formulas - P (O) (OR ⁴⁶ ) (OR ⁴⁷ ) or - (CO) _i NR ⁴⁹ R ⁵⁰ , where R ⁴⁶ and R ^{47 are the} same or different and mean hydrogen, methyl or ethyl, j means the number 0 or 1, R ⁴⁹ and R ^{50 are the} same or different and mean hydrogen or m ethyl and / or these heterocycles may be substituted by linear or branched alkyl containing up to 3 carbon atoms, which may have from one to two, identical or different, substituents: hydroxy, carboxyl or the residue of the formula -P (O) (OR ⁵³ ) (OR ⁵⁴ ), where R ⁵³ and R ^{54 are the} same or different and are hydrogen, methyl or ethyl, and / or said heterocycles may contain N-linked piperidinyl or pyrrolidinyl as a substituent, R ⁵ represents hydrogen, R ⁶ represents ethoxy or propoxy, and their salts, hydrates, N-oxides and isomeric forms. 3. 2-Phenyl-substituted imidazotriazinones of the 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] triazin-4 -he, 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 it 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] triazin-4 -one in the form of dihydrochloride, 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -one in the form of a hydrochloride trihydrate, 2- [2-ethoxy-5- (4-methylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he, 2- [2-ethoxy-5- (4-cyclopentylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he, 2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2 , 4] triazin-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-he 5-methyl-2- (5-morpholin-4-sulfonyl) -2-ethoxyphenyl] -7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4-one, 2- [2-ethoxy-5- (4-hydroxypiperidin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazin-4 -he, N, N-diethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4] triazin-2-yl ) benzenesulfamide, N-propyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] - [1,2,4 ] triazin-2-yl) benzenesulfonamide. 4. 2-Phenyl-substituted imidazotriazinone of the general formula (I) according to claim 1, which is 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] - [1,2,4] triazin-4-one, its salts and hydrates. 5. 2-Phenyl-substituted imidazotriazinone of the general formula (I) according to claim 1, which is 2- [2-ethoxy-5- (4-ethylpiperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5.1-f] - [1,2,4] triazin-4-one, its hydrochloride and hydrochloride trihydrate. 6. Phenyl substituted imidazotriazinones of the general formula (I) according to claim 1, having phosphodiesterase inhibitory activity I, II and V. 7. The method of obtaining 2-phenyl substituted imidazotriazinones according to claim 1, characterized in that the compound of General formula (II)

in which R ¹ and R ² have the above meaning, 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)

wherein R ⁵ and R ⁶ have the above meaning, in systems ethanol and phosphorus oxychloride / dichloroethane and the resulting compound of General formula (IV)

wherein R ¹ , R ² , R ⁵ and R ⁶ have the above meaning, subjected to interaction with chlorosulfonic acid, followed by the interaction of the resulting compound of General formula (V)

wherein R ¹ , R ² , R ⁵ and R ⁶ have the above meaning, with an amine of the general formula (VI)

in which R ³ and R ⁴ have the above meaning, in an inert solvent and the selection of the target product. 8. A drug having the properties of an inhibitor of phosphodiesterases I, II and V, containing an active substance and pharmacologically acceptable agents, characterized in that the active substance contains compounds of the general formula (I) according to claim 1 or their salts, hydrates, N- oxides and isomeric forms. 9. The drug 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] triazin-4-one, a salt or hydrate thereof. 10. The drug according to 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] triazin-4-one, or its hydrochloride or hydrochloride trihydrate. Feature priority: 12.11.1997 - have all the meanings of the radicals R ¹ - R ⁶ , with the exception of values relating to a) formed by the radicals R ³ and R ⁴ together with the nitrogen atom of the heterocycles substituted with tetrazolyl, b) formed by the radicals R ⁷ and R ⁸ together with the nitrogen atom of the triazolyl and residues of the formula

c) triazolyl formed by the radicals R ³⁴ and R ³⁵ together with the nitrogen atom, which take priority from 10/31/1998 by the filing date of application PCT / EP 98/06910.