2-Phenyl-substituited Imidazotriazinones as Phoshodiesterase Inhibitors

(54) (56)

AGENT

NAME

Bayer AG, 51368 Leverkusen DE

Ulrich Niewöhner, Wermelskirchen DE, Mazen Es-Sayed, Langenfeld DE, Helmut Haning, Wuppertal DE, Thomas Schenke, Bergisch Gladbach DE, Karl-Heinz Schlemmer, Wuppertal DE, Jörg Keldenich, Wuppertal DE, Erwin Bischoff, Wuppertal DE, Elisabeth Perzborn, Wuppertal DE, Klaus Dembowsky, Boston MA US, Peter Serno, Bergisch Gladbach DE, Marc Nowakowski, Wuppertal DE

Albihns Stockholm AB

2-Phenyl-substituted imidazotriazinones as phosphodiesterase inhibitors (57)

MENTIONED PUBLICATIONS:

WO Al 9 42S 902 (A61K 31/505), WO Al 9 161 657 (A61K 31- / 505), DE Al 2 811 780 (C07D 487/04)

SUMMARY:

2-Phenyl-substituted imidazotriazinones having short, unbranched alkyl groups in the 9-position of the general formula (1) are prepared from the corresponding 2-phenylimidazotriazinones by chlorosulfonation and then reaction with amines. The compounds inhibit cGMP-metabolising phosphodiesterases and are suitable as active substances in drugs, for the treatment of cardiovascular and cerebrovascular diseases and / or diseases of the urogenital system, especially for the treatment of erectile dysfunction.

The numbers in parentheses indicate international identification code, INID code. Letter in parentheses indicates international document code.

522 809

Summary

2-Phenyl-substituted imidazotriazinones having short, unbranched alkyl groups in the 9-position of general formula (I) are prepared from the corresponding 2-phenylimidazotriazinones by chlorosulfonation and then reaction with amines. The compounds inhibit cGMP-metabolising phosphodiesterases and are suitable as active substances in medicaments, for the treatment of cardiovascular and cerebrovascular diseases and / or diseases of the urogenital system, in particular for the treatment of erectile dysfunction.

522 809

The invention relates to 2-phenyl-substituted imidazotriazinones, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolising phosphodiesterases.

Offenlegungsschrift DE 28 11 780 describes imidazotriazines as bronchodilators with spamolytic activity and inhibitory activity against cyclic adenosine monophosphate metabolising phosphodiesterases (cAMP-PDEs, nomenclature according to Beavo: PDE-III and PDE-IV). An inhibition of cyclic guanosine monophosphate metabolizing phosphodiesterases (cGMP-PDEs, nomenclature of Beavo and Reifsnyder (Trends 10 in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) is not described. No compounds containing a sulfonamide group in the 2-position aryl radical are claimed. Furthermore, imidazotriazinones are described in FR 22 13 058,

CH 59 46 71, DE 22 55 172, DE 23 64 076 and EP 000 9384, which in the 2-position have no substituted aryl residue, and which are also described as bronchodilators with cAMP-PDE inhibitory activity.

WO 94/28902 describes pyrazolopyrimidinones which are suitable for the treatment of impotence.

The compounds of the invention are potent inhibitors of either one or more of the cyclic guanosine 3 ', 5'-monophosphate metabolizing phosphodiesterases (cGHPPDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

An increase in the cGMP concentration may lead to beneficial antiaggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilating, natriuretic and diuretic effects. It may affect short-term or long-term modulation of vascular and cardiac inotropin, heart rhythm and cardiac conduction (JC

Stoclet, T. Keravis, N. Komas, and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).

522 809 DD;

The present invention relates to 2-phenyl-substituted imidazotriazinones of the general formula (I)

<img file="SE522809C2_D0001.tif" />

R¹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R² denotes straight-chain alkyl having up to 4 carbon atoms,

R³ and R⁴ is the same or different and denotes hydrogen or straight chain or branched alkenyl or alkoxy having in either case up to 8 carbon atoms or denotes a straight chain or branched alkyl chain having up to 10 carbon atoms, which is optionally interrupted by an oxygen atom and which is optionally substituted one to several times, the same or different with trifluoromethyl, trifluoromethoxy, hydroxy, halogen, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms and / or having residues of the formulas -SO 3 H, - (A) a -NR⁷R⁸, -O-CO-NR⁷'R⁸', -S (O) bR⁹, -pcoxor '^ or¹¹),

<img file="SE522809C2_D0002.tif" />

<img file="SE522809C2_D0003.tif" />

wherein a and b are the same or different and the number is 0 or 1,

A is a residual CO or SO₂,

R⁷, R⁷, R⁸ and R⁸ are the same or different and denote hydrogen

522 809 or denotes cycloalkyl having 3-8 carbon atoms, aryl having 6-10 carbon atoms, a 5-6 membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms selected from S, N and / or O, wherein the above the ring systems are optionally substituted one to several times the same or different with hydroxy, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 6 carbon atoms or having a group of formula - (SO₂)_C-NR¹²R¹³, where c is the number 0 or 1,

R¹² and R¹³ are the same or different and represent hydrogen or straight chain or branched alkyl having up to 5 carbon atoms or

R⁷, R⁷, R⁸ and R⁸ denotes straight-chain or branched alkoxy having up to 6 carbon atoms, or straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted one or more times the same or different with hydroxy, halogen, aryl with

6-10 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 6 carbon atoms or having a group of the formula - (CO)_d-NR^I4R¹⁵, whereby

R¹⁴ and R¹⁵ is the same or different and denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and d is the number 0 or 1, or

R⁷ and R⁸ and / or R⁷ and R⁸ together with the nitrogen atom forms a 5-7 membered, saturated heterocycle, which may optionally contain an additional heteroatom selected from S or O or a residue of formula -NR¹⁶, whereby

R¹⁶ represents hydrogen, aryl having 6-10 carbon atoms, benzyl, a 5-7 membered aromatic or saturated heterocycle having up to 3 heteroatoms selected from

522 809

S, N and / or O, which is optionally substituted by methyl, or denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy,

R⁹ denotes aryl having 6-10 carbon atoms or denoted straight chain or branched alkyl having up to 4 carbon atoms,

R¹⁰ and R¹¹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and / or wherein the one above under R³/ R⁴ The alkyl chain indicated is optionally substituted with cycloalkyl of 3-8 carbon atoms, aryl of 6-10 carbon atoms or with a 5-7 membered, partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle, which may contain up to 4 heteroatoms selected from S, N , 0 or a residue of formula -NR, wherein

R represents hydrogen, hydroxy, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in both cases up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted one to several times, the same or different from hydroxy, or with straight-chain or branched alkoxy having up to 6 carbon atoms, and wherein ayl and the heterocyclic group are optionally substituted one to several times, the same or different with nitro, halogen, -SO 3 H, with straight-chain or branched alkyl or alkoxy having in both cases up to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy and / or with a residue of the formula -SO 2 NR¹⁸R¹⁹, whereby

R¹⁸ and R¹⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and / or

R³ or R⁴ represents a group of formula NR²⁰R²¹, there

R²⁰ and R²¹ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these, and / or

522 809

R³ or R⁴ denotes adamantyl or denotes the residues by the formulas:

<img file="SE522809C2_D0004.tif" />

or represents cycloalkyl of 3-8 carbon atoms, aryl of 6-10 carbon atoms or represents a 5-7 membered, partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle, which may contain up to 4 heteroatoms selected from S, N, O or a residue of formula -NR²², whereby

R²² has the above meaning of R¹⁶ and is the same as or different therefrom or represents carboxyl, formyl or straight-chain or branched acyl having up to 5 carbon atoms, and wherein cycloalkyl, aryl and / or the heterocyclic group are optionally substituted one to several times, the same or different with halogen, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight chain or branched acyl or with alkoxycarbonyl having up to 6 carbon atoms throughout, nitro and / or with the groups of the formulas -SO₃H, -OR²³, (SO₂)_eNO²⁴R²⁵, -P (O) (OR²⁶) (OR²⁷), where e is the number 0 or 1,

R is a residue of formula

Or denotes cycloalkyl having 3-7 carbon atoms or hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted

522 809 with cycloalkyl having 3-7 carbon atoms, benzyloxy, tetrahydropyranyl, tetrahydrofuranyl, straight chain or branched alkoxy or alkoxycarbonyl having up to 6 carbon atoms throughout, carboxyl, benzyloxycarbonyl or with phenyl which in turn may be substituted one to several times the same or different with straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxy or halogen, and / or alkyl optionally substituted by radicals of the formulas

-CO-NR²⁸R²⁹ or -CO-R³⁰, wherein io R²⁸ and R²⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or

R²⁸ and R²⁹ together with the nitrogen atom forms a 5-7 membered saturated heterocycle, which may optionally contain an additional heteroatom S or O, and

R³⁰ is phenyl or adamantyl,

R²⁴ and R²⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these,

R²⁶ and R²⁷ has the above meaning of R¹⁰ and R¹¹ and are the same as these or different, and / or cycloalkyl, aryl and / or the heterocyclic group are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, carboxyl, with a 5-7 articulated heterocycle having up to 3 heteroatoms, selected from S, N and / or O or having the groups of formula -SO₂-R³¹, P (O) (OR³²) (OR³³) or -N³⁴R³⁵, whereby

R³¹ denotes hydrogen or has the meaning given above by R⁹ and is the same as this or different,

R and R have the meaning given above of R and R and are the same as or different from these,

522 809

R³⁴ and R³⁵ is the same or different and denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy or with straight-chain or branched alkoxy having up to 4 carbon atoms, or

R³⁴ and R³⁵ together with the nitrogen atom forms a 5-6 membered saturated hetero5 cycle, which may contain an additional heteroatom selected from S and O or a residue of formula -NR, wherein

R³⁶ denotes hydrogen, hydroxy, straight-chain or branched alkoxycarbonyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 5 io carbon atoms, which is optionally substituted by hydroxy, or

R³ and R⁴ together with the nitrogen atom forms a 5-7 membered, unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle, which may optionally contain up to 3 heteroatoms selected from S, N, O or a residue with³⁷, whereby

R represents hydrogen, hydroxy, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy, or alkoxycarbonyl having through to up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted one to several times, the same or different with hydroxy, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 6 carbon atoms or with the groups of formula - (D)_rNO³⁸R³⁹, -CO- (CH2) gO-CO-R⁴⁰, -CO- (CH2)_hrs-OR⁴¹ or-P (O) (OR⁴²) (OR⁴³), where g and h are the same or different and denote a number 1, 2, 3 or 4, and f is a number 0 or 1,

D is a group of formula -CO or -SO₂,

R³⁸ and R³⁹ are the same or different and have the meaning given above by R⁷ and

R⁸,

R⁴⁰ denotes straight-chain or branched alkyl having up to 6 carbon atoms,

522 809 .ifU

...........

R⁴¹ denotes straight-chain or branched alkyl having up to 6 carbon atoms,

R⁴² and R⁴³ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R³⁷ is a residue of formula - (CO) jE, where i is the number 0 or 1,

E represents cycloalkyl having 3-7 carbon atoms or benzyl, aryl having 6-10 carbon atoms or a 5-6 membered aromatic heterocycle having up to 4 heteroatoms from the group S, N and / or O, the above ring systems being optionally substituted with a to several times, equal or different with nitro, halogen, -SO₃H, straight-chain or branched alkoxy having up to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy or with a residue of formula -SO₂-NR⁴⁴R⁴⁵, whereby

R⁴⁴ and R⁴⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as these or different therefrom, or

E denotes residues with the formulas

CH

-Ν N — CH, v_y ³ or - | / j \ - / and the one under R³ and R⁴ The heterocycle formed together with the nitrogen atom is optionally substituted one to several times the same or different, possibly also geminally, with hydroxy, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl with in both cases up to 6 carbon atoms, with nitro and with groups of the formulas -P (O) (OR⁴⁶) (OR⁴⁷),

522 809

<img file="SE522809C2_D0005.tif" />

= NO⁴or - (CO) jNR⁴'R^!°, wherein

R⁴⁶ and R⁴⁷ has the above meaning of R¹⁰ and R¹¹ and are the same as or different from these,

R⁴⁸ represents hydroxy or straight-chain or branched alkoxy having up to 4 carbon atoms, the number is 0 or 1, and

R⁴⁹ and R⁵⁰ are the same or different and have the meaning given above by R¹⁴ and R¹⁵, and / or the one under R³ and R⁴ The heterocycle formed together with the nitrogen atom is optionally substituted with straight-chain or branched alkyl having up to 6 carbon atoms, which in turn is optionally substituted one to several times equal or different with hydroxy, halogen, carboxyl, cycloalkyl or cycloalkyloxy with in both cases 3 -8 carbon atoms, with straight-chain or branched alkoxy or alkoxy carbonyl having in either case up to 6 carbon atoms or with a residue of formula -SO₃H, -NR⁵¹R⁵² or P (O) OR⁵³OR⁵⁴, whereby

R⁵¹ and R⁵² are the same or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and have the meaning given above by R¹⁰ and R¹¹, and / or wherein alkyl is optionally substituted with aryl having 6-10 carbon atoms, which in turn may be substituted one to several times, the same or different with halogen, hydroxy, straight chain or branched alkoxy having up to 6 carbon atoms or with a group of formula -NR R, wherein

R and R have the meaning given above of R and R and are the same as or different from these, and / or the one below R³ and R⁴ The heterocycle formed together with the nitrogen atom is optionally substituted with aryl having 6-10 carbon atoms or with

522 809 pHUOU Ub i:

a 5-7 membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms selected from S, N and / or O, optionally also linked by a bifunction, wherein the ring systems may in turn be substituted by hydroxy or by straight chain or branched alkyl or alkoxy with in both cases up to 6 carbon atoms more, or

R³ and R⁴ together with the nitrogen atom form residues with the formulas

<img file="SE522809C2_D0006.tif" />

R⁵ and R⁶ are the same or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxy or straight-chain or branched alkoxy having up to 6 carbon atoms, as well as the salts, hydrates, N-oxides and the isomeric forms of these compounds.

The compounds of the invention may exist in stereoisomeric forms, which behave either as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention encompasses both the enantiomers or diastereomers as well as their respective mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a manner known per se.

The substances according to the invention may also be present as salts. Within the scope of the invention, physiologically harmless salts are preferred.

522 809 pHMUU Ub l

Physiologically harmless - or safe - salts may be salts of the compounds of the invention with inorganic or organic acids. Preferred are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, tolanesulfonic acid.

Physiologically harmless or safe salts may also be metal or ammonium salts of the compounds of the invention. Particularly preferred are, for example, sodium, potassium, 10m magnesium or calcium salts and ammonium safr, which are derived from ammonia or organic amines, for example ethylamine, di- or triethylamine, di- and triethanolamine, dicycklohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

Heterocyclic group, optionally benzocondensed, is according to the invention generally a saturated, partially unsaturated or unsaturated 5-7 membered heterocycle, which may contain up to 4 heteroatoms, selected from S, N and / or O. Examples include; azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, morinol, imidoline piperazinyl, N-methylpiperazinyl or piperidinyl. Preferred are quinolyl, furyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, piperazinyl, azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.

A straight-chain or branched acyl radical having 1-6 carbon atoms is within the scope of the invention, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Preferred is a straight-chain or branched acyl group having 1-4 carbon atoms. Particularly preferred are acetyl and ethylcarbonyl.

A straight-chain or branched alkoxy radical having 1-6 and 1-4 carbon atoms, respectively, is within the scope of the invention methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and

522 809 n-hexoxy. Preferred is a straight-chain or branched alkoxy group having 1-6, 1-4 and 1-3 carbon atoms, respectively, especially preferred is a straight-chain or branched alkoxy group having 1-3 carbon atoms.

A straight-chain or branched alkoxycarbonyl radical having 1-6 carbon atoms is within the scope of the invention, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Preferred is a straight chain or branched alkoxycarbonyl radical having 1-4 carbon atoms. Particularly preferred is a straight or branched alkoxycarbonyl radical having 1-3 carbon atoms.

io

A straight-chain or branched alkyl radical having 1-4, 1-6, 1-8 and 1-10 carbon atoms is within the scope of the invention, for example methyl, ethyl, n-propyl, isopropyl, tert, butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preferred are straight-chain or branched alkyl groups having 1-3, 1-4 and 1-8 carbon atoms, respectively. Particularly preferred are straight-chain or branched alkyl groups having 1-4 and 1-3 carbon atoms, respectively.

Straight chain alkyl having up to 4 carbon atoms within the scope of the invention are, for example, methyl, ethyl, n-propyl and n-butyl.

²⁰ (C 1 -C 10) -aryl is generally an aromatic residue having 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl.

Cycloalkyl having 3-8 and 3-7 carbon atoms, respectively, according to the invention are, for example, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. As preferred may be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.

Cycloalkyloxy having 3-8 carbon atoms according to the invention are cyclopropyloxy, cyclopentyloxy, cyclobutyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy. As preferred may be mentioned: cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

Halogen within the scope of the invention are generally fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine. And especially preferred are fluorine and chlorine.

522 809

A 5-6 membered and 7-membered saturated heterocycle, respectively, which may contain an additional heteroatom selected from S, N and / or O are within the scope of the invention and depend on the above substituents, for example morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrofuranyl . Preferred are morpholinyl, tetrahydropyranyl, piperidinyl and piperazinyl.

A 5-6 membered aromatic heterocycle having up to 3 or 4 heteroatoms, selected from S, O and / or N, is within the scope of the invention, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preferred are pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.

A 5-6 membered unsaturated, partially unsaturated or saturated heterocycle, which may contain up to 3 and 4 heteroatoms, respectively, selected from S, O and / or N, are within the scope of the invention e.g. pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl, piperidinyl, piperazinyl or morpholinyl. Preferred are pyridyl, pyrimidyl, piperazinyl, pyridazinyl, morpholinyl, furyl and thiazolyl.

The compounds of the invention, especially the salts, may also be present as hydrates. Within the scope of the invention, hydrates are to be understood as meaning compounds which contain crystalline water. Such compounds may contain one or more, typically 1-5, equivalents of water. Hydrates can be prepared, for example, by crystallizing the compound in question from water or from an aqueous solvent. Preferred are compounds of the invention of general formula (I), wherein

R¹ denotes straight-chain or branched alkyl having up to 3 carbon atoms,

R² denotes straight-chain alkyl having up to 3 carbon atoms,

R³ and R⁴ are the same or different and represent hydrogen or straight chain or branched alkenyl or alkoxy having in either case up to 6 carbon atoms or denote a straight chain or branched alkyl chain having up to 8 carbon atoms, which may be interrupted by an oxygen atom and which may be substituted one to three times the same or different with hydroxy, fluorine, chlorine, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms and / or with residues

522 809

......

with the formulas -SO₃H, - (A)_A-NR⁷R⁸, -O-CO-NR⁷R⁸', -S (O)_b-R⁹,

-P (O) (OR¹⁰) (ORⁿ),

<img file="SE522809C2_D0007.tif" />

wherein a and b are the same or different and denote a number 0 or 1,

A denotes a residue CO or SO₂,

R⁷, R⁷, R⁸ and R⁸ are the same or different and represent hydrogen or represent cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, the above ring systems being optionally substituted one to three times, equal or different with hydroxy, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 4 carbon atoms or having a group of formula - (SO₂)_c-NR¹²R¹³, where c is a number 0 or 1,

R¹² and R¹³ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R⁷, R⁷, R⁸ and R⁸ is straight-chain or branched alkoxy having up to 3 carbon atoms or denotes straight-chain or branched alkyl having up to 7 carbon atoms, optionally substituted one or more times, the same or different with hydroxy, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl with in both cases up to 4 carbon atoms or with a group of formula - (CO)_d-NR¹⁴R¹⁵,

522 809 • · ·

• «·» varvid

R¹⁴ and R¹⁵ are the same or different and denote hydrogen or straight chain or branched alkyl having up to 3 carbon atoms, and d is a number 0 or 1, or

R⁷ and R⁸ and / or R⁷ and R⁸ together with the nitrogen atom forms a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl ring or represents radicals of the formulas

N:

N

CH, x:

-O

hrs₃C

N-R¹⁶ or

4-R¹⁶ wherein

R¹⁶ represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or denotes straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxy,

R⁹ denotes straight-chain or branched alkyl having up to 3 carbon atoms,

R¹⁰ and R¹¹ is the same or different and denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and / or the one under R³/ R⁴ the alkyl chain indicated is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, quinolyl, pyrrolidinyl, pyrimidyl, morpholinyl, furyl, piperidinyl, tetrahydrofuranyl or by residues of the formulas or

522 809; av.

::: ν · .. ·· .. ·.:.

wherein

R¹⁷ denotes hydrogen, hydroxy, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in either case up to 3 carbon atoms, or denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted one to three times, equal or different with hydroxy , or with straight-chain or branched alkoxy having up to 4 carbon atoms and wherein phenyl and the heterocyclic groups are optionally substituted one to three times, the same or different with nitro, fluorine, chlorine, -SO 3 H, with straight-chain or branched alkyl or alkoxy having in both cases up to 4 carbon atoms, with hydroxy, and / or with a residue of the formula -SO2-NR¹⁸R¹⁹, whereby

R¹⁸ and R¹⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and / or

R³ or R⁴ denotes a group of formula -NR²⁰R²¹, there

R²⁰ and R²¹ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these, and / or

R³ and R⁴ denotes adamantyl or denotes residues of the formulas

<img file="SE522809C2_D0008.tif" />

522 809 η :: ·::: 17 ::: ·.

-O-^RE . -O,, 0 whereby

R has the meaning of R above and is the same as or different therefrom, or represents carboxyl, formyl or straight-chain or branched acyl having up to 3 carbon atoms, and wherein cycloalkyl, phenyl and / or the heterocyclic groups are optionally substituted by one to three times, the same or different with fluorine, chlorine, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in both cases up to 5 carbon atoms, nitro and / or with groups of the formulas -SO₃H, OR²³, (SO₂)_eNO²⁴R²⁵, -P (O) (OR²⁶) (OR²⁷), where e is a number 0 or 1,

R represents a radical of the formula or represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or cycloheptyl hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, benzyloxy, tetrahydropuroxyranyl, grenadrahydro-pyranyl, or alkoxycarbonyl having in both cases up to 4 carbon atoms, benzyloxycarbonyl in »» I

522 809 pry00-05 · in or with phenyl, which in turn may be substituted one to several times, the same or different, with straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxy, fluorine or with chlorine, and / or alkyl optionally substituted with residues of the formulas 5 -CO-NR²⁸R²⁹ or -CO-R³⁰, whereby

R and R are the same or different and represent hydrogen or straight chain or branched alkyl having up to 5 carbon atoms or

R²⁸ and R²⁹ together with the nitrogen atom forms a morpholinyl, pyrrolidinyl or piperidinyl ring, io and

R³⁰ denotes phenyl or adamantyl,

R²⁴ and R²⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these,

R and R have the meaning given above of R and R and are the same as or different from these, and / or represent cycloalkyl, phenyl and / or the heterocyclic groups are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which optionally substituted with hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or with groups of the formulas -SO 2 -R³¹, P (O) (OR³²) (OR³³) or NR³⁴R³⁵, whereby

9

R has the above meaning of R and is the same as this or different therefrom,

33 10 11

R and R have the meaning given above of R and R and are the same as or different from these,

R³⁴ and R³⁵ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxy or with straight-chain or branched alkoxy having up to 3 carbon atoms, or

R³⁴ and R³⁵ together with the nitrogen atom forms a morpholinyl, triazolyl or thiomorpholinyl ring or a residue of formula

<img file="SE522809C2_D0009.tif" />

522 809 varvid

R³⁶ represents hydrogen, hydroxy, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy, or

R³ and R⁴ together with the nitrogen atom forms a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring or a residue of formula

-N MR³⁷ wherein

R³⁷ denotes hydrogen, hydroxy, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms throughout, or denotes straight-chain or branched alkyl having up to 5 carbon atoms, optionally substituted one to three times, equal or different with hydroxy , trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 4 carbon atoms or having groups of the formulas - (D)_rNO³⁸R³⁹, -CO- (CH2) gO-CO-R⁴⁰, -CO- (CH2)_hrs-OR⁴¹ or -P (O) (OR⁴²) (OR⁴³), where g and h are the same or different and denote the number 1, 2 or 3, and f is the number 0 or 1,

D represents a group of formula -CO or -SO₂,

R³⁸ and R³⁹ are the same or different and have the meaning given above by R⁷ and R⁸,

R⁴⁰ denotes straight-chain or branched alkyl having up to 4 carbon atoms,

R⁴¹ denotes straight-chain or branched alkyl having up to 4 carbon atoms,

R⁴² and R⁴³ are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

522 809 ΩΧ. ·;

................

R represents a residue of formula - (CO) jE, where i is the number 0 or 1,

E represents cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, the above ring systems being optionally substituted one to two times equal or different with nitro, fluorine, chlorine, -SO 3 H, straight chain or branched alkoxy having up to 4 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy or with a residue of the formula -SCh-NR⁴⁵, whereby

R⁴⁴ and R⁴⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as these or different therefrom, or

E denotes residues with the formulas

-N N-CH₃ or \ _y

<img file="SE522809C2_D0010.tif" />

and those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted one to three times the same or different, optionally also geminally, with hydroxy, formyl, carboxyl, straight chain or branched acyl or alkoxycarbonyl having up to 5 carbon atoms in both cases, with nitro and groups having the formulas -P (O) (OR⁴⁶) (OR⁴⁷), o == NR⁴⁸ or - (CO) jNR⁴⁹R⁵⁰ wherein

R⁴⁶ and R⁴⁷ has the above meaning of R¹⁰ and R¹¹ and are the same as or different from these, * 48

R represents hydroxy or straight chain or branched alkoxy having up to 3 carbon atoms,

522 809 j is a number 0 or 1, and

R⁴⁹ and R⁵⁰ are the same or different and have the meaning given above by R¹⁴ and R¹⁵, and / or those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted with straight-chain or branched alkyl having up to 5 carbon atoms, which may in turn be substituted one to several times, the same or different with hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 4 carbon atoms or having a residue of the formula -SO 3 H, -NR⁵¹R⁵² or P (O) OR⁵³OR⁵⁴, whereby

R⁵¹ and R⁵² are the same or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in both cases up to 4 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and have the meaning given above by R¹⁰ and R¹¹, and / or wherein alkyl is optionally substituted with phenyl, which in turn may be substituted one to three times, the same or different with fluorine, chlorine, hydroxy, straight chain or branched alkoxy having up to 4 carbon atoms or with a group of formula NR⁵¹ R⁵², whereby

R⁵¹ and R⁵² has the above meaning of R⁵¹ and R⁵² and are the same as or different from these, and / or those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also linked over an N function, the ring systems in turn being substituted by hydroxy or by straight-chain or branched alkyl or alkoxy with in both cases up to 5 carbon atoms, or

R³ and R⁴ together with the nitrogen atom form residues with the formulas:

522 809

^._n⁺/ (CH₂)₃-CH₃

<img file="SE522809C2_D0011.tif" />

<img file="SE522809C2_D0012.tif" />

or

<img file="SE522809C2_D0013.tif" />

R⁵ and R⁶ are the same or different and represent hydrogen, hydroxy or straight chain or branched alkoxy having up to 4 carbon atoms, as well as the salts, N-oxides, hydrates and the isomeric forms of these compounds.

Particularly preferred are compounds of the invention of general formula (I), wherein

R¹ denotes a straight-chain or branched alkyl having up to 3 carbon atoms,

R² denotes a straight chain alkyl having up to 3 carbon atoms,

R³ and R⁴ is the same or different and denotes hydrogen or straight chain or branched alkenyl or alkoxy having in either case up to 4 carbon atoms or denotes a straight chain or branched alkyl chain having up to 6 carbon atoms, which may be interrupted by an oxygen atom and which may be substituted one to three times, equal or different with hydroxy, fluorine, chlorine, carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms and / or with residues of the formulas

-SO₃H, - (A)_A-NR⁷R⁸, -O-CO-NR⁷'R⁸', -S (O)_b-R⁹, -P (O) (OR¹⁰) (OR¹),

O

<img file="SE522809C2_D0014.tif" />

522 809 HHyUU-Ub · I:

wherein a and b are the same or different and denote a number 0 or 1,

A represents a residue CO or SO 2,

R, R, R and R are the same or different and represent hydrogen or represent cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, the above ring systems being optionally substituted one to two times, the same or different with hydroxy, nitro, carboxyl , fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 3 carbon atoms, or having a group of formula - (SO2)_C-NR¹²R¹³, where c is a number 0 or 1,

R¹² and R¹³ are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R, R, R and R represent methoxy or denote straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted once or twice, equal or different with hydroxy, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in both cases up to 3 carbon atoms or with a group of formula - (CO) d-NR¹⁴R¹⁵, whereby

R¹⁴ and R¹⁵ are the same or different and represent hydrogen, methyl or ethyl, and d is a number 0 or 1, or

R and R and / or R and R together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or radicals of the formulas

522 809

CH

IN

Ν == ι

ΛΛ —-NS h, c

-N ^ \ lR¹⁶ or no¹⁶ whereby, 16

R represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or represents straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxy,

R⁹ denotes methyl,

R¹⁰ and R¹¹ are the same or different and represent hydrogen, methyl or ethyl, and / or the one under R³/ R⁴ the alkyl chain indicated is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl or by radicals of the formulas / - \

OO or -N NO¹⁷,

II \ _ /

X wherein

R represents hydrogen, hydroxy, formyl, acetyl or alkoxy having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted one to two times, the same or different with hydroxy, or with straight-chain or branched alkoxy having up to 3 carbon atoms, and wherein phenyl and the heterocyclic groups are optionally substituted one to three times, the same or different, with fluorine, chlorine, -SO 3 H, with straight-chain or branched alkyl or alkoxy having in both cases up to 3 carbon atoms, with hydroxy, and / or with a residue of formula -SO₂NO¹⁸R¹⁹, whereby

522 809

R¹⁸ and R¹⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and / or

R³ or R⁴ denotes a group of formula -NR²⁰R²¹, there

21 18 19

R and R have the meaning given above of R and R and are the same as or different from these, and / or

R³ or R⁴ denotes adamantyl or denotes the residues by the formulas:

<img file="SE522809C2_D0015.tif" />

6’'5 ,

<img file="SE522809C2_D0016.tif" />

so.

<img file="SE522809C2_D0017.tif" />

x '

OH

00, or

O

<img file="SE522809C2_D0018.tif" />

or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetra20 hydropyranyl or residues of the formulas

<img file="SE522809C2_D0019.tif" />

<img file="SE522809C2_D0020.tif" />

<img file="SE522809C2_D0021.tif" />

522 809

<img file="SE522809C2_D0022.tif" />

wherein

R²² has the above meaning of R¹⁶ and is the same or different therefrom or represents formyl or acetyl and wherein cycloalkyl, phenyl and / or the heterocyclic groups are optionally substituted one to two times, equal or different with fluorine, chlorine, triazolyl, carboxyl, straight chain or branched acyl or alkoxycarbonyl having in both cases up to 4 carbon atoms, with nitro and / or with groups of the formulas -SO₃H, -OR²³, (SO₂)_eNO²⁴R²⁵, -P (O) (OR²⁶) (OR²⁷), where e is a number 0 or 1,

R²³ represents a residue of the formula or represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, straight-chain or branched alkoxy with up to 3 carbon atoms, benzyloxycarbonyl or with phenyl, which in turn may be substituted one to two times, the same or different with methoxy, hydroxy, fluorine or chlorine, and / or alkyl is optionally substituted with the radicals of the formulas -CO-NR²⁸R²⁹ or -CO-R³⁰, whereby

R and R are the same or different and represent hydrogen or straight chain or branched alkyl having up to 4 carbon atoms or

R²⁸ and R²⁹ together with the nitrogen atom forms a morpholinyl, pyrrolidinyl or piperidinyl ring and

R³⁰ denotes phenyl or adamantyl,

522 809

R²⁴ and R²⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these,

<img file="SE522809C2_D0023.tif" />

27 . 1011

R and R have the meaning given above of R and R and are the same or different from these, and / or cycloalkyl, phenyl and / or the heterocyclic groups are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which in their is optionally substituted by hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by the groups of the formulas -SO₂-R³¹, P (O) (OR³²) (OR³³) or NR³⁴R³⁵, io varvid

R³¹ denotes methyl,

R and R have the meaning given above of R and R and are the same as or different from these,

R³⁴ and R³⁵ are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which are optionally substituted by hydroxy or methoxy, or

R³⁴ and R³⁵ together with the nitrogen atom forms a morpholinyl, triazolyl or thiomorpholinyl ring or a residue of formula wherein

R³⁶ represents hydrogen, hydroxy, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms, optionally substituted by hydroxy, or

R³ and R⁴ together with the nitrogen atom forms a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring or a residue of formula

<img file="SE522809C2_D0024.tif" />

where

522 809 ppUOO OS i

R represents hydrogen, hydroxy, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in either case up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted one to two times, equal or different with hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 3 carbon atoms or having groups of formula - (D)_rNO³⁸R³⁹, -CO- (CH2) gO-CO-R⁴⁰, -CO- (CH2) h-OR⁴¹ or -P (O) (OR⁴²) (OR⁴³), where g and h are the same or different and denote a number 1 or 2, io and f are the number 0 or 1,

D represents a group of formula -CO or -SO₂,

R³⁸ and R³⁹ are the same or different and have the meaning given above by R⁷ and

R⁸, is R⁴⁰ denotes straight-chain or branched alkyl having up to 3 carbon atoms,

R⁴¹ denotes straight-chain or branched alkyl having up to 3 carbon atoms,

R⁴² and R⁴³ are the same or different and represent hydrogen, methyl or ethyl, or

R³⁷ is a residue of formula - (CO) iE, where i is the number 0 or 1,

E represents cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, the above ring systems being optionally substituted one to two times, the same or different with nitro, fluorine, chlorine, -SO₃H, straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxy, or with a residue of formula -SO₂-NR⁴⁴R⁴⁵, whereby

R⁴⁴ and R⁴⁵ has the above meaning of R¹⁸ and R¹⁹ and are the same as or different from these, or

E denotes residues with the formulas

522

809

<img file="SE522809C2_D0025.tif" />

-N ^ -CH₃ or and those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted one to three times the same or different, optionally also geminally, with hydroxy, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in either case up to 3 carbon atoms, or with groups having the formulas -P (O) (OR⁴⁶) (OR⁴⁷), io

<img file="SE522809C2_D0026.tif" />

= NO⁴⁸ or - (CO) jNR⁴⁹R⁵⁰, whereby

R⁴⁶ and R⁴⁷ has the above meaning of R¹⁰ and R¹¹ and are the same as or different from these,

R represents hydroxy or methoxy, j is a number 0 or 1, and

R⁴⁹ and R⁵⁰ are the same or different and have the meaning given above by R¹⁴ and R¹⁵, and / or those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn is optionally substituted one to three times the same or different by hydroxy, fluorine, chlorine, carboxyl, cyclopropyl, cyclo25 heptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 3 carbon atoms or having a residue of formula -SO₃H, -NR^3lR⁵² or

P (O) OR⁵³OR⁵⁴, whereby

R⁵¹ and R⁵² are the same or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in both cases up to 3 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and have the meaning given above by R¹⁰ and R¹¹,

522 809 and / or alkyl is optionally substituted with phenyl, which in turn may be substituted one to two times, the same or different with fluorine, chlorine, hydroxy, methoxy or with a group of formula -NR R, wherein

R and R have the meaning given above of R and R and are the same as or different from these, and / or those under R³ and R⁴ the heterocyclic groups formed together with the nitrogen atom are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also linked over a io N function, wherein the ring systems may in turn be substituted by hydroxy or by straight-chain or branched alkyl or alkoxy with in both cases up to 3 carbon atoms, or

R³ and R⁴ together with the nitrogen atom form residues with the formulas

<img file="SE522809C2_D0027.tif" />

R⁵ and R⁶ are the same or different denote hydrogen, hydroxy or straight chain or branched alkoxy having up to 3 carbon atoms, as well as the salts, the N-oxides, the hydrates and the isomeric forms of these compounds,

Particularly preferred are compounds of general formula (I), wherein R^l represents methyl or ethyl,

R represents ethyl or propyl,

522 809 pp0: 00,000

R³ and R⁴ are the same or different and denote a straight-chain or branched alkyl chain having up to 5 carbon atoms which is optionally substituted up to two times the same or different with hydroxy or methoxy, or

R³ and R⁴ together with the nitrogen atom forms a piperidinyl, morpholinyl, thiomor · folinyl ring or a residue of formula

-N_N-R³⁷ io varvid

R represents hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl having in either case up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted one to two times, the same or different with hydroxy, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in either case up to 3 carbon atoms or having groups of the formulas - (D)_rNO³⁸R³⁹ or -P (O) (OR⁴²) (OR⁴³), where f is a number 0 or 1,

D represents a group of formula -CO,

R³⁸ and R³⁹ are the same or different and denote hydrogen or methyl,

R⁴² and R⁴³ are the same or different and represent hydrogen, methyl or ethyl, or

R represents cyclopentyl and those below R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted one to two times, equal or different, optionally also geminally, with hydroxy, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in either case up to 3 carbon atoms or with groups of the formulas -P (O) (OR⁴⁶) (OR⁴⁷) or - (CO) iNR⁴⁹R⁵⁰, whereby

R⁴⁶ and R⁴⁷ are the same or different and represent hydrogen, methyl or ethyl, j is a number 0 or 1,

522 809 ::: ·.· ·..··..· .

and

R⁴⁹ and R⁵⁰ are the same or different and represent hydrogen or methyl, and / or those under R³ and R⁴ The heterocyclic groups formed together with the nitrogen atom are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which are optionally in turn substituted once or twice, the same or different by hydroxy, carboxyl or by a radical of formula P (O ) OR⁵³OR⁵⁴, whereby

R⁵³ and R⁵⁴ are the same or different and denote hydrogen, methyl or ethyl, io and / or those under R³ and R⁴ the heterocyclic groups formed together with the nitrogen atom are optionally substituted by N-linked piperidinyl or pyrrolidinyl,

R⁵ denotes hydrogen, and

R⁶ denotes ethoxy or propoxy, and the salts, hydrates, N-oxides and isomeric forms of these compounds.

Also compounds of the invention of the general formula (I) are especially preferred, for which R⁵ denotes hydrogen and the residues R⁶ and -SO₂NO³R⁴ are in a position in relation to each other at the phenyl ring.

522 809

Particularly preferred compounds are those listed in Table A:

io

Table A:

<img file="SE522809C2_D0028.tif" />

522 809

<img file="SE522809C2_D0029.tif" />

522 809

<img file="SE522809C2_D0030.tif" />

522 809

<img file="SE522809C2_D0031.tif" />

522 809

<img file="SE522809C2_D0032.tif" />

In addition, a process has been found for the preparation of the compounds of the general formula (I) according to the invention, which is characterized in that to a complex compounds of the general formula (II)

<img file="SE522809C2_D0033.tif" />

where

R¹ and R² has the meaning given above and and

L denotes straight-chain or branched alkyl having up to 4 carbon atoms, with compounds of general formula (III)

<img file="SE522809C2_D0034.tif" />

where

R⁵ and R⁶ has the meaning given above, according to a two-step reaction in the systems ethanol and phosphorus oxytrichloride / dichloroethane are converted into compounds of the general formula (IV)

522 809 • · • · • · • · » ·

<img file="SE522809C2_D0035.tif" />

R¹, R², R⁵ and R⁶ has the meaning given above, and in a further step is reacted with chlorosulfonic acid to compounds of general formula (V)

<img file="SE522809C2_D0036.tif" />

where

R¹, R², R⁵ and R⁶ has the meaning given above, after which it is finally reacted with amines of the general formula (VI)

HN³R⁴ (VI) there

R³ and R⁴ has the meaning given above, in inert solvents.

The process according to the invention can be illustrated by way of example with the following formula scheme:

522 809

<img file="SE522809C2_D0037.tif" />

<img file="SE522809C2_D0038.tif" />

HC1

Ethanol

Phosphorus oxytrichloride / dichloroethane

<img file="SE522809C2_D0039.tif" />

Suitable solvents for the individual steps are ordinary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethymethorethylmethurethylmethaneformyl, trichloroethymethrene, , acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of them

522 809 ΡκυϋϋΌ5 · 1 said solvents. Particularly preferred are ethanol for the first stage and dichloroethane for the second stage.

The reaction temperature can generally be varied within wide limits. In general, work is carried out in the temperature range from -20 ° C to 200 ° C, preferably from 0 ° C to

70 ° C.

The process steps of the invention are generally carried out at normal pressure. However, it is also possible to work at overpressure or at underpressure (eg in the range from 0.5 to 5 bar).

The reaction of the compounds of the general formula (V) takes place in the temperature range from 0 ° C to room temperature and at normal pressure.

The reaction with the amines of general formula (VI) is carried out in one of the above chlorinated hydrocarbons, preferably in dichloromethane.

The reaction temperature can generally be varied within wide limits. In general, one works in the range from -20 ° C to 200 ° C, preferably from 0 ° C to room temperature.

The turnover is generally carried out at normal pressure. However, it is also possible to carry out the reaction under overpressure or under underpressure (eg in the range from 0.5 to 5 bar).

The compounds of the general formula (II) are partially known or new and can be prepared by compounds of the general formula (VII)

R²-CO-T (VII) there

R has the meaning given above and

T represents halogen, preferably chlorine, to a beaker by reaction with compounds of general formula (VIII)

R

HO₂C^/+ NH₂ (VIII) there

R¹ has the meaning given above in inert solvents, optionally in the presence of a base and trimethylsilyl chloride, are converted into compounds of the general formula (IX) r-co-nh co₂h (IX) there

R¹ and R² has the meaning given above, and then reacted with the compound of formula (X)

O where L has the meaning given above, in inert solvents, possibly in the presence of a base.

Suitable solvents for the individual steps of the process are the usual organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloromethylene, trichloromethylene, , acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the solvents mentioned. Especially preferred for that

522 809 the first step is dichloromethane and for the second step a mixture of tetrahydrofuran and pyridine.

Suitable bases are generally alkali hydrides or alcoholates such as sodium hydride or potassium tert-butylate or cyclic amines such as piperidine, pyridine, dimethylaminopyridine or C₄-alkylamines, eg triethylamine. Preferred are triethylamine, pyridine and / or dimethylaminopyridine.

The base is generally added in an amount of 1-4 moles, preferably 1.2-3 moles, calculated per 10 moles of the compound of formula (X).

The reaction temperature can generally be varied within wide limits. In general, work in the range from -20 ° C to 200 ° C, preferably from 0 ° C to 100 ° C.

The compounds of general formulas (VII), (VIII), (IX) and (X) are known per se or can be prepared by conventional methods.

The compounds of general formula (III) can be prepared by compounds of general formula (XI)

<img file="SE522809C2_D0040.tif" />

where

R⁵ and R⁶ has the meaning given above, is reacted with ammonium chloride in toluene and in the presence of trimethylaluminum in hexane in the temperature range from -20 ° C to room temperature, preferably at 0 ° C and normal pressure, after which the amidine formed, optionally in situ, is reacted with hydrazine hydrate.

The compounds of general formula (XI) are known per se or can be prepared by conventional methods.

522 809 b-Ly / UU-Ub · 1

The compounds of general formula (IV) are partially known or also novel and can be prepared according to known methods [cf. David R. Marshall, Chemistry and Industry, May 2, 1983, 331-335].

The compounds of the general formula (V) are in themselves new and can be prepared from the compounds of the general formula (IV) according to the publication Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1974, p. 338-339.

The compounds of the invention of general formula (I) have a non-predictable, valuable pharmacological spectrum of action.

They inhibit either one or more of the c-GMP metabolizing phosphodiesterases (PDE I, PDE II and PDE V). This leads to an increase in c-GMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs as well as the differentiated subcellular localization of these enzymes together with the selective inhibitors according to the invention enable a selective addressing of the various processes regulated by c-GMP.

In addition, the compounds of the invention enhance the effect of substances, e.g.

EDRF (Endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances which, in a way other than phosphodiesterase inhibitors, increase the c-GMP concentration.

The compounds can thus be used in drugs for the treatment of cardiovascular diseases such as for the treatment of high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, further for the treatment of thromboembolic diseases and ischemias such as myocardial infarction, stroke, ischemic attacks , angina pectoris, peripheral bleeding disorders, prevention of restenosis after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTC A) and bypass. Furthermore, they can be important for cerebrovascular diseases. The relaxing effect on the smooth muscles makes the compounds suitable for the treatment of

522 809 diseases of the urogenital system such as prostate hypertrophy, incontinence and especially for the treatment of erectile dysfunction and sexual dysfunction in women.

Phosphorus diesterase (PDE) activity.

c-GMP-stimulated PDE II, c-GMP-inhibited PDE III and cAMP-specific PDE IV were isolated from either porcine or bovine myocardium. The Ca²⁺-calmodulin-stimulable PDE I was isolated from porcine aorta, porcine brain or preferably from bovine aorta. The c-GMP-specific PDE V was obtained from porcine intestine, porcine aorta, human blood cells and preferably from bovine aorta. The purification was by anion exchange chromatography over MonoQ® from Pharmacia, mainly according to the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Volume 40, 193-202 (1990) and C. Lugman et al. Biochemical Pharmacology Volume 35 17431751 (1986).

The determination of the enzyme activity was performed in a test batch of 100 μΐ in 20 mM Tris / HCl · buffer pH 7.5, which contained 5 mM MgCl₂, 0.1 mg / ml bovine serum albumin and either 800 Bq ³HcAMP or ³HcGMP. The final concentration of the corresponding nucleotides is 10 *⁶ mol / 1st The reaction is started by adding the enzyme and the enzyme amounts are adjusted so that during the incubation time of 30 minutes about 50% of the substrate is reacted. To test the cGMP-stimulated PDE II is used as a substrate³HcAMP and the batch are added with IO⁶ mol / l of unlabeled cGMP. For testing of Ca²⁺-calmodulin-dependent PDE I, the reaction batch is also added with CaCl₂ 1 μΜ and calmodulin 0.1 μΜ. The reaction is stopped by adding 100 μ 100 of acetonitrile, which contains 1 mM cAMP and 1 mM AMP. 100 μΐ of the reaction batch is separated on HPLC and the cleavage products are quantitatively determined "Online" with a flow-through scintillation counter. The substance concentration is measured, at which the reaction rate is reduced by 50%. In addition, for the testing “Phosphodiesterase [³H] cAMP-SPA enzyme assay ”and“ Phosphodiesterase [³H] cGMP-SPA enzyme assay ”from Amersham Life Science. The test was performed according to the experimental protocol specified by the petitioner. For the activity determination of PDE II, [³H] cAMP-SPA assay, with the reaction batch being added

522 809

ΙΟ '⁶ Μ cGMP for activation of the enzyme. To measure PDE I, calmodulin 10 'was added⁷ M and CaCl₂ 1 μΜ to the reaction kit. PDEV was measured with [³H] cGMP SPA assay.

Inhibition of phosphodiesterases in vitro

<td>Example no</td><td>PDEI ICsUnMl</td><td>PDE ICsUnM]</td><td>PDEV</td>

<td> 16</td><td> 300</td><td> &gt;1000</td><td> 2</td>

<td> 19</td><td> 200</td><td> &gt;1000</td><td> 2</td>

<td> 20</td><td> 200</td><td> &gt;1000</td><td> 2</td>

<td> 26</td><td> 100</td><td> &gt;1000</td><td> 1</td>

<td> 27</td><td> 200</td><td> &gt;1000</td><td> 3</td>

<td> 32</td><td> 100</td><td> &gt;1000</td><td> 4</td>

<td> 260</td><td> 300</td><td> &gt;1000</td><td> 10</td>

<td> 275</td><td> 50</td><td> &gt;1000</td><td> 3</td>

<td> 338</td><td> 200</td><td> &gt;1000</td><td> 5</td>

In principle, the inhibition of one or more phosphodiesterases of this type leads to an increase in the cGMP concentration. Thereby, the compounds are of interest for all types of therapy, in which an increase in the cGMP concentration can be considered useful or healthy.

The study of the cardiovascular effects was performed with SH rats and dogs. The substances were applied intravenously or orally.

The reaction-triggering study was performed on awake rabbits [H. Naganuma, T. Egashira, J. Fuji, Clinical and Experimental Pharmacology and Physiology 20, 177-183 (1993)]. The substances were applied intravenously, orally or parenterally.

The new active substances and their physiologically harmless or unobtrusive salts (eg hydrochlorides, maleinates or lactates) can be transferred in a known manner to common preparations such as tablets, dragees, pills, granules, aerosols, syrups,

522 809 PhUOO OS In emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. In this case, the therapeutically active compound should be present in a concentration of about 0.5-90% by weight of the total mixture, ie in amounts sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by mixing the active substances with solvents and / or carriers, optionally using emulsifiers and / or dispersants, whereby, for example, in the case of using water as diluent, organic solvents may optionally be used as co-solvents.

The application takes place in the usual way, preferably orally, transdermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or by inhalation.

For use in humans, a dosage of 0.001-50 mg / kg, preferably 0.01-20 mg / kg, is suitably administered orally. For parenteral administration, eg nasally through the mucous membranes, buccally or by inhalation, a dose of 0.001-0.5 mg / kg is suitably used.

However, it may be necessary to deviate from the mentioned amounts, namely depending on the body weight and type of application, further depending on individual conditions towards the drug, further depending on the type of formulation and the time and intervals for the administration. Thus, in some cases a smaller amount than the above-mentioned minimum amount may suffice, while in other cases the said upper limit must be exceeded. In the case of application of larger amounts, it may be advisable to distribute these in several single doses throughout the day.

The compounds of the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts may be administered in a suitable formulation, in accordance with all veterinary practice of the PhUUU U ::? · Men. The veterinarian can determine the type of use and dosage depending on the type of animal being treated.

starting Compounds

Example IA

2-butyrylaminopropionsyra

<img file="SE522809C2_D0041.tif" />

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. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise and the solution is stirred for 1 hour at room temperature and for 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.

Under ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred for 15 minutes at room temperature. The aqueous phase is evaporated to dryness and the residue is triturated with acetone and the mother liquor is filtered off with suction. After removal of the solvent, the residue is chromatographed. The resulting product is dissolved in 3 N sodium hydroxide solution and the resulting solution is evaporated to dryness. The substance is taken up in concentrated HCl and evaporated again to dryness. The substance is stirred with acetone, the precipitated solid is filtered off with suction and the solvent is removed in vacuo. You receive

28.2 g (71%) of a tough oil, which crystallizes after a while.

200 1 H NMR (DMSO-d 6): 0.84, 84 3H; 1.22, d, 3 H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin, 1H; 8.09, d, 1 H.

522 809

Example 2A

2-butyrylamino-butyric acid

<img file="SE522809C2_D0042.tif" />

CH₃

25.78 g of 2-aminobutyric acid (250 mmol) 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 mmol) of trimethylsilyl chloride are then added dropwise and the solution is stirred for 1 hour at room temperature and for 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.

For mild ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred for 15 minutes at room temperature. The organic phase is added with sodium hydroxide solution and the organic solvent is removed in vacuo. After acidification, the precipitated solid is stirred once with water and twice with petroleum ether, then dried in vacuo at 45 ° C. 29.1 g (67%) of a colorless solid are obtained.

200 MHz 1 H-NMR (DMSO-d 6): 0.88, t, 6H; 1.51, quart., 2H; 1.65, m. 2H; 2.09, t, 2H; 4.10, m, 1 H; 8.01, d, 1 H; 12.25, s, m 1H.

522 809

Example 3A

2-ethoxybenzonitrile

<img file="SE522809C2_D0043.tif" />

g (210 mmol) of 2-hydroxybenzonitrile are refluxed overnight with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone. The solid is filtered off, the solvent is removed in vacuo and the residue is distilled in vacuo. 30.0 g (97%) of a colorless liquid are obtained.

200 MHz ¹ 1 H-NMR (DMSO-d 6: 1.48, t, 3H; 4.15, quart., 2H; 6.99, dζ 2H; 7.51, dt, 2H.

Example 4A

2-etoxibensamidinhydroklorid

<img file="SE522809C2_D0044.tif" />

CIH

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

The cooled reaction mixture is added under ice-cooling 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. It is aspirated and washed with the same amount of methanol. The mother liquor is evaporated and the residue obtained is stirred with a mixture of dichloromethane and methanol (9: 1), the solid is filtered off with suction and the mother liquor is evaporated. 30.4 g (76%) of a colorless solid are obtained.

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

Example 5A

2-propoxibensonitril

<img file="SE522809C2_D0045.tif" />

g (630 ml) of 2-hydroxybenzonitrile is refluxed overnight with 174 g (1.26 mol) of potassium carbonate and 232.2 g (1.89 mol) of ethyl bromide in 11 acetone. The solid is filtered off, the solvent is removed in vacuo and the residue is distilled off in vacuo.

Bp: 89 ° C (0.7 mbar)

Yield: 95.1 g (93.7%)

Example 6A

2-propoxybenzamidine hydrochloride

hrs₃C 0 H NH

<img file="SE522809C2_D0046.tif" />

522 809 ρρ; ιηη. · ;; ::;. ;

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 2 M solution of triethylaluminum in hexane are added dropwise and the mixture is stirred at room temperature until the evolution of gas ceases. After adding 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture is stirred overnight at 80 ° C (bath). The cooled reaction mixture is added under ice-cooling to a suspension of 300 g of silica gel and 2.85 l of ice-cooled chloroform, and the mixture is stirred for 30 minutes. It is aspirated and washed with the same amount of methanol. The solvent is distilled off in vacuo, the residue is stirred in 500 ml of a mixture of dichloromethane and methanol (9: 1), the solid is filtered off and the mother liquor is evaporated. The residue is stirred with petroleum ether, after which it is filtered off with suction. You receive

22.3 g (52%) of product.

^!1 H-NMR (200 MHz, CD₃OD): 1.05 (3H); 1.85 (sex, 2H); 4.1 (A, 2H); 7.0-7.2 (m. 2H); 7.5 - 7.65 (m, 2H).

Example 7A

2-ethoxy-4-methoxybenzonitrile

<img file="SE522809C2_D0047.tif" />

30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are refluxed for 18 hours in 550 ml of acetone together with 83.4 g of potassium carbonate (603 mmol) and 32.88 g (301 mmol) of bromomethane. After filtration, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel (cyclohexane: ethyl acetate = 10: 1). 35.9 g of an oil are obtained.

R_f= 0.37 (cyclohexane: ethyl acetate = 3: 1)

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

7.48, d, 1H.

522 $09

Example 8A

2-ethoxy-4-metoxibensamidinhydroklorid

<img file="SE522809C2_D0048.tif" />

1 H

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

The cooled reaction mixture is added under 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. It is aspirated and washed with the same amount of methanol. The mother liquor is evaporated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9: 1), the solid is filtered off with suction and the mother liquor is evaporated. The residue is stirred with petroleum ether and then filtered off with suction. 7.95 g (50%) of solid are obtained.

200 MHz 1 H-NMR (DMSO-d 6): 1.36, t, 3H; 3.84, s. 3H; 4.15, quart., 2H; 6.71, m, 2 H; 7.53, d, 1H, 8.91, s, fold, 3H.

Example 9A

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

<img file="SE522809C2_D0049.tif" />

522 809

The starting material is 24.4 g (0.186 mol) of N-acetyl-D, L-alanine in 200 ml of abs. tetrahydrofuran and add 45 ml of abs. pyridine and 0.5 g of 4-dimethylaminopyridine. Heat to reflux and add 51.85 g (0.372 mol) of oxalic acid monoethyl ester chloride dropwise.

Heat for another 90 minutes to reflux, cool, pour the substance into ice water, extract three times with ethyl acetate. The organic phase is dried over sodium sulphate, evaporated and the substance is taken up in 62.5 ml of methanol. 9 g of sodium bicarbonate are added, the mixture is stirred at reflux for 2.5 hours and filtered.

To a solution of 38.26 g (190.65 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in

250 9.54 g (190.65 mmol) of hydrazine hydrate are added dropwise under ice-cooling and the resulting suspension is stirred for a further 30 minutes at room temperature. To the reaction mixture is added the methanol solution described above and stirred for 4 hours at 70 ° C bath temperature. After filtration, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo.

The residue is taken up in 250 ml of 1,2-dichloroethane, 32.1 ml (348 mmol) of phosphorus oxychloride are added dropwise and the mixture is heated to reflux for two hours. It is cooled, evaporated, the substance is taken up in a small amount of methylene chloride, diethyl ether is added and the solid is sucked off. Chromatograph on silica gel (methylene chloride / methanol 95: 5), evaporate the solution and stir the crystalline residue with diethyl ether. Yield: 8.1 g (14.9% of theory).

200 MHz 1 H-NMR (CDCl 3)₃): 1.58, t, 3H; 2.62, s. 3H; 2.68, s. 3H; 4.25, q, 2H; 7.04, d, 1 H; 7,12,11H; 7.5, dt, 1 H; 8.19, dd, 1 H; 10.02, s, 1H.

522 809

........

Example 10A

2- (2-ethoxy-phenyl) -5-methyl-7-propyl-3H-imidazo [5,1] [1,2,4] thinazin-4-one

<img file="SE522809C2_D0050.tif" />

7.16 g (45 mmol) of 2-butyrylamino-propionic acid are dissolved with 10.67 g of pyridine in 45 ml of THF and after the addition of a spatula tip DMAP is heated to reflux. 12.29 g (90 mmol) of oxalic acid-ethyl ester chloride are added slowly and dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice water, extracted three times with ethyl acetate, dried over sodium sulfate and rotated. The residue is taken up in 15 ml of ethanol and boiled together with 2.15 g of sodium bicarbonate

2.5 hours to reflux. The cooled solution is filtered.

To a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol is added dropwise under ice-cooling 2.25 g (45 mmol) of hydrazine hydrate and the resulting suspension is stirred for 10 minutes at room temperature. To this reaction mixture is added the ethanol solution described above and then stirred for 4 hours at 70 ° C bath temperature. After filtration, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo.

The residue is dissolved in 60 ml of 1,2-dichloroethane and, after adding 7.5 ml of phosphorus oxychloride, it is refluxed for 2 hours. Dilute with dichloromethane and by adding sodium bicarbonate solution and solid sodium bicarbonate the mixture is neutralized. The organic phase is dried and the solvent is removed in vacuo. Chromatography with ethyl acetate and crystallization gives 4.00 g (28%) of a colorless solid, Rf = 0.42 (dichloromethane / methanol = 95: 5).

522 809

200 MHz 1 H-NMR (CDCl 3): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3 H;

3.00, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1 H; 8.17, dd, 1H; 10.00, s, 1H.

Example 11A

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

<img file="SE522809C2_D0051.tif" />

7.16 g (45 mmol) of 2-butyrylaminopropionic acid are dissolved together with 10.67 g of pyridine in 45 ml of tetrahydrofuran and after the addition of a spatula tip dimethylaminopyridine are boiled to reflux. 12.29 g (90 mmol) of oxalic acid ethyl ester chloride are added slowly and dropwise and the mixture is refluxed for 3 hours. The mixture is poured into ice water, extracted three times with ethyl acetate, dried over sodium sulphate and stirred. The residue is taken up in 15 ml of ethanol and boiled together

2.15 g of sodium bicarbonate 2.5 hours at reflux. The cooled solution is filtered.

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

The residue is dissolved in 60 ml of 1,2-dichloroethane and, after adding 7.5 ml of phosphorus oxychloride, it is refluxed for 2 hours. Dilute with dichloromethane and by adding

522 809 sodium bicarbonate solution and solid sodium bicarbonate are neutralized. The organic phase is dried and the solvent is removed in vacuo. Crystallization from ethyl acetate gives 2.85 g (19.1%) of a yellow solid and chromatographic purification of the mother liquor gives an additional 1.25 g (8.4%) of the product.

Rf = 0.45 (dichloromethane / methanol = 95: 5).

<img file="SE522809C2_D0052.tif" />

Example 12A

2- (2-ethoxy-4-methoxyphenyl) -5-methyl-7-propyl-377-imidazo [5, L / J [l, 2,4] triazine-4-one

CH.

HRS.

5.50 g (34.8 mmol) of 2-butyrylaminopropionic acid are dissolved with 8.19 g of pyridine in 35 ml of tetrahydrofuran and after the addition of a spatula tip dimethylaminopyridine is boiled to reflux. 9.43 g (69 mmol) of oxalic acid ethyl ester chloride are added slowly and dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice water, extracted three times with ethyl acetate, dried over sodium sulfate and rotated. The residue is taken up in 11 ml of methanol and boiled with 1.65 g of sodium hydrogen carbonate for 2.5 hours at reflux. 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 is added dropwise under ice-cooling 1.73 g (34.5 mmol) of hydrazine hydrate and the resulting suspension is stirred for a further 30 minutes at rumstem3030 ratur. To the reaction mixture is added the methanolic solution described above and stirred for 4 hours at 70 ° C bath temperature. After filtration, the residue is partitioned between dichloroethane and water, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo.

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

Rf = 0.46 (dichloromethane / methanol - 20: 1).

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.03, ζ 3H; 1.58, ζ 3H; 1.88, m. 2H; 2.62, s. 3H; 2.98,

<img file="SE522809C2_D0053.tif" />

s, 1H.

Example 13A

2- (2-ethoxyphenyl) -5-ethyl-7-propyl-3/7-imidazo [5, lf] [l, 2,4] triazine-4-one

HRS.

‘3

CH.

29.06 g (167.8 mmol) of 2-butyrylaminobutyric acid are dissolved together with 39.76 g of pyridine in 170 ml of tetrahydrofuran and after the addition of a spatula tip dimethylaminopyridine the mixture is heated to reflux. 45.81 g (335.5 mmol) of oxalic acid ethyl ester chloride are added slowly and dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice water, extracted three times with ethyl acetate, dried over sodium sulfate and rotated. The residue is taken up in 15 ml of methanol and half of the solution is boiled together with 7.96 g of sodium bicarbonate for 2.5 hours at reflux. The cooled solution is filtered.

522 809

To a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzoic acid amide hydrochloride in 85 ml of ethanol is added dropwise under ice-cooling 4.20 g (83.9 mmol) of hydrazine hydrate and the resulting suspension is stirred for 10 minutes at room temperature. To this reaction mixture is added the methanolic solution described above and stirred

4 hours at 70 ° C bath temperature. After filtration, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo.

The residue is dissolved in 112 ml of 1,2-dichloroethane and, after adding 14 ml of phosphorus oxychloride, it is boiled for 2 hours at reflux. Dilute with dichloromethane and neutralize by adding sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed in vacuo. Chromatography (dichloromethane: methanol = 50: 1) gives 3.69 g (12.4%) of a colorless solid,

Rf = 0.46 (dichloromethane / methanol = 20: 1).

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

Example 14A

4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) bensensulfonsyraklorid

<img file="SE522809C2_D0054.tif" />

The starting material is 7.25 g (25.5 mmol) of 2- (2-ethoxyphenyl) -5,7-dimethyl-3H-imidazo [5.1f] [1,2,4] -triazin-4-one and adding under ice-cooling 26.74 g (0.23 mol) of chlorosulfonic acid. Stir overnight at room temperature, pour the mixture into ice water, aspirate the crystals and dry them in a vacuum desiccator.

Yield: 9.5 (97% of theory)

200 MHz ^l1 H-NMR (d⁶-DMSO): 1.32, t, 3H; 2.63, s. 3H; 2.73, s, 3 H; 4.13, q, 2H;

7.15, d, 1 H; 7.77, m, 2 H; 12.5, s, 1H.

Example 15A 10 4-Ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) benzenesulfonic acid chloride

<img file="SE522809C2_D0055.tif" />

2.00 g (6.4 mmol) of 2- (2-ethoxy-phenyl) -5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazine 4-one is slowly added to 3.83 ml of chlorosulfonic acid at 0 ° C. The reaction mixture is stirred overnight at room temperature, then poured into ice water and extrahaled with dichloromethane. 2.40 g (91%) of colorless foam are obtained.

200 MHz 1 H-NMR (CDCl 3)₃): 1.03, t, 3H; 1.61, 2H; 1.92, hex, 2H; 2.67, s, 3 H;

3.10, 2H; 4.42, quart., 2H; 7.27, t, 1 H; 8.20, dd, 1 H; 8.67, d, 1 H; 10.18, s, 1H.

522 809

Example 16A

4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) bensensulfonsyraklorid

<img file="SE522809C2_D0056.tif" />

2.80 g (8.6 mmol) 2- (2-propoxy-phenyl) -5-methyl-7-propyl-3H-imidazo [5,1-lf] [1,2,4] triazin-4-one is slowly added to 5.13 ml of chlorosulfonic acid at 0 ° C. The reaction mixture is stirred overnight at room temperature, then poured into ice water and extrahaled with dichloromethane. 3.50 g (96%) of colorless foam are obtained.

Rf = 0.49 (dichloromethane / methanol = 95: 5)

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.03, 2t, 6H; 1.95, m, 4 H; 2.81, s. 3H; 3.22, t, 2H;

4.11, 2H; 7.09, m, 1 H; 8.06, dd, 1 H; 8.21, m, 1H; 12.0, s, 1H.

Example 17A

4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) bensensulfonsyraklorid

<img file="SE522809C2_D0057.tif" />

S = O él

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

R_f = 0.50 (dichloromethane / methanol - 20: 1)

200 MHz 1 H-NMR (CDCl 3)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, 1 H; 8.72, s, 1 H; 9.75, s, 1 H.

Example 18A 10 4-Ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] -triazin-2-yl) benzenesulfonic acid chloride

<img file="SE522809C2_D0058.tif" />

1.70 g (5.21 mmol) 2- (2-ethoxy-phenyl) -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine-4- is slowly added to 3.12 ml of chlorosulfonic acid at 0 ° C. The reaction mixture is stirred overnight at room temperature, then poured into ice water and extracted with dichloromethane. 2.10 g (94%) of colorless foam are obtained.

400 MHz 1 H-NMR (CDCl 3)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, 1 H; 8.19, dd, 1 H; 8.70, d, 1 H;

10.08, s, brett, 1H.

522 809

Example 19A (4-Piperidinylmethyl) -phosphonic acid diethyl ester

<img file="SE522809C2_D0059.tif" />

The starting material is 2.11 g (528 mmol) of 60% sodium hydride in 50 ml of abs. tetrahydrofuran and add dropwise 15.7 g (52.8 mmol) of methanediphosphonic acid diethyl ester. Stir for an additional 30 minutes at room temperature and then add 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone dropwise. The mixture is stirred for one hour at room temperature and one hour under reflux, after which it is evaporated, water is added, extracted three times with dichloromethane, dried over sodium sulphate and evaporated. The residue is hydrogenated in 50 ml of ethanol over 1.7 g of 10% palladium-activated carbon at room temperature and 3 bar. The catalyst is filtered off with suction and the filtrate is evaporated.

Yield: 12.5 g (100% of theory)

400 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.13, m, 2H; 1.32, ζ 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-furoxankarbaldehyd

<img file="SE522809C2_D0060.tif" />

40 g (571 mmol) of crotonaldehyde are dissolved in 80 ml of acetic acid and at 0 ° C a solution of 137 g (1.99 mol) of sodium nitrite in 300 ml of water is added dropwise. Stir for 2 hours at room temperature, then dilute with 800 ml of water and extract 3 times

522 809 with dichloromethane. After drying the organic phase, 13.8 g (18.9%) of 5-methyl-4-furoxanecarbaldehyde are obtained by chromatography (cyclohexane / ethyl acetate).

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

Example 21A

5-methyl-4-fluoroxanecarboxylic acid chloride io

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

6.92 g of the residue is refluxed for 6 hours together with 10 ml of thionyl chloride in 20 ml of dichloromethane. It is diluted with toluene, filtered and rotated. The residue is taken up again in dichloromethane, added with 10 ml of thionyl chloride and refluxed for 48 hours. The solvent is removed in vacuo and the residue is distilled in vacuo. 2.00 g (25%) of colorless crystals are obtained.

200 MHz 1 H-NMR (CDCl 3)₃): 2.41, p.

522 809

Example 22A 1- (5-Methyl-4-furoxanecarbonyl) -4-tert-butyloxycarbonyl-piperazine

<img file="SE522809C2_D0061.tif" />

2.75 g (14.7 mmol) of Boc-piperazine are dissolved together with 1.49 g of triethylamine in 20 ml of dichloromethane and added portionwise at 0 ° C with 2.00 g (12.3 mmol) of 5-methyl-410-furoxanecarboxylic acid chloride. Stir for 30 minutes at 0 ° C and 2 hours at room temperature, then dilute with dichloromethane and wash with water. The solvent is removed in vacuo and the residue is purified by chromatography (cyclohexane / ethyl acetate). 3.33 g (87%) of 1- (5-methyl-4-furoxanecarbonyl) -4-tert-butyloxycarbonyl-piperazine are obtained.

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

3.87, m. 2H.

Example 23A 1- (5-Methyl-4-furoxanecarbonyl) -piperazine trifluoroacetate

<img file="SE522809C2_D0062.tif" />

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

522 809 PRUOU U ::&gt; &lt;

200 MHz 1 H-NMR (DMSO-d 6): 2.18, s, 3H; 3.18, m, 2 H; 3.25, m, 2 H; 3.83, m. 2H; 3.90, m, 2 H; 8.89, s, fold, 2H.

Preparation example

Example 1

2- [2-ethoxy-5- (4-methyl-piperazine-l-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5, lf] [l, 2,4] triazine-4-one

<img file="SE522809C2_D0063.tif" />

<img file="SE522809C2_D0064.tif" />

IN

CH₃

0.1 g (0.26 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride is dissolved in 10 ml of dichloromethane and cooled to 10 ° C. After the addition of a spatula tip DMAP, 80 mg (0.784 mmol) of N-methylpiperazine are added and the reaction mixture is stirred overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution, dried over sodium sulphate and the solvent is removed in vacuo. Chromatography on silica gel (dichloromethane / methanol 9: 1).

Yield: 40 mg (34.5% of theory)

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

522 809

Example 2

2- [2-ethoxy-5- (4-hydroxyethylpiperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1]] - [1,2,4] triazin-4-one

<img file="SE522809C2_D0065.tif" />

<img file="SE522809C2_D0066.tif" />

OH

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2- yl) -benzenesulfonic acid chloride and 100 mg (0.784 mmol) of 4-hydroxypiperazine 45 mg (36.1% of theory) 2- [2-ethoxy-5- (4-hydroxy-ethylpiperazine-1-sulfonyl) -phenyl] -5.7 37 ¥ dimethyl-imidazo [5,1-f] [l, 2,4] triazine-4-one

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

522 809

Example 3

2- [2-ethoxy-5- (4-hydroxypiperidine-l-sulfonyl) -phenyl] -5,7-dimethyl-3/7-imidazo [5, lf] [l, 2,4] triazine-4-one

HRS.

<img file="SE522809C2_D0067.tif" />

OH

<img file="SE522809C2_D0068.tif" />

N

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 80 mg (0.784 mmol) 4-hydroxypiperidine 35 mg (29.8% of theory) 2- [2-ethoxy-5- (4-hydroxy-piperidine-1-sulfonyl) -phenyl] -5,7- dimethyl-3H-imidazo [5,1] [1,2,4] triazin-4-one.

200 MHz 1 H-NMR (CDCl 3)₃): 1.61, t, 3H; 1.69, m, 2H; 1.94, m. 2H; 2.67, s, 3 H;

<img file="SE522809C2_D0069.tif" />

dd, 1H; 8.52, d. 1H; 9.73, s, 1 H.

522 809

Example 4

2- [2-ethoxy-5- (4-hydroxymethylpiperidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3Himidazo [5,1]] - [1,2,4] triazin-4-one

<img file="SE522809C2_D0070.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine 22 mg (18% of theory) 2- [2-ethoxy-5- (4-hydroxy-methylpiperidine-1-sulfonyl) -phenyl] -5, 7-dimethyl-37 / -imidazo [5, lf] [l, 2,4] triazin-4-one.

200 MHz * 1 H-NMR (CDCl 3)₃): 1.38, dt, 2H; 1.62, t, 3H; 1.82, dd, 2H; 2.35, dt, 2 H; 2.78, s. 3H; 2.84, s. 3H; 3.5, d, 2H; 3.87, d, 2H; 4.39, q, 2H; 7.21, d, 1 H; 7.95, dd, 1 H; 8.51, d. 1H; 10.03, bs, 1H.

522 809

Example 5

2- [2-ethoxy-5- (3-hydroxypyrrolidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1]] [1,2,4] triazin-4-one

<img file="SE522809C2_D0071.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2- yl) -benzenesulfonic acid chloride and 70 mg (0.784 mmol) 3-hydroxypyrrolidine 13 mg (11.1% of theory) 2- [2-ethoxy-5- (3-hydroxy-pyrrolidine-1-sulfonyl) -phenyl] -5.7 -dimethyl-377-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-dihydro-imidazo [5,1]] [1,2,4] triazine- 2-yl) benzenesulfonamide

CH.

'3

CH.

<img file="SE522809C2_D0072.tif" />

522 809

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 70 mg (0.784 mmol) of 2- (ethylamino) -ethanol 23 mg (20.1% of theory) 4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5 , 7-dimethyl-4-oxo-3,4-dihydroimidazo- [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonamide.

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

Example 7

N, N-diethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) -benzenesulfonamide

<img file="SE522809C2_D0073.tif" />

hrs₃C N / CH₃

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride 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-3,4-dihydroimidazo [5 f] [l, 2,4] triazine-2-yl) -benzenesulfonamide.

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

522 809

Example 8

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

<img file="SE522809C2_D0074.tif" />

‘3

CH.

<img file="SE522809C2_D0075.tif" />

<img file="SE522809C2_D0076.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 130 mg (0.784 mmol) of 1- (2-pyrimidinyl) -piperazine 38 mg (28.2% of theory) 2- [2-ethoxy-5- (4- (2-pyrimidinyl) - piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-37 H-imidazo [5,1] [1,2,4] triazin-4-one.

<img file="SE522809C2_D0077.tif" />

<img file="SE522809C2_D0078.tif" />

bs, 1H.

522 809

Example 9

2- [2-ethoxy-5- (morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1]] [1,2,4] triazin-4-one

<img file="SE522809C2_D0079.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 70 mg (0.784 mmol) morpholine 28 mg (24.2% of theory) 2- [2-ethoxy-5- (morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3/7 imidazo [5, lf] [l, 2,4] triazin-4-one.

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

Example 10

2- [2-ethoxy-5- (1,4-dioxa-6-azaspiro [4,4] nonane-6-sulfonyl) -phenyl] -5,7-dimethyl-3,7-imidazo [5,1] [1] , 2,4] triazine-4-one

<img file="SE522809C2_D0080.tif" />

522 809 PRUOO OS l

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 100 mg (0.784 mmol) of 1,4-dioxa-6-azaspiro [4.4] nonane 45 mg (35.3% of theory) 2- [2-ethoxy-5- (1,4- dioxa-6-azaspiro [4,4] nonane-6-sulfonyl) -phenyl] -5,7-dimethyl-3,7-imidazo [5,1-f] [1,2,4] triazin-4-one .

200 MHz 1 H-NMR (CDCl 3)₃): 1.58, ζ 3H; 2.02, t, 2H; 2.61, s. 3H; 2.65, s. 3H; 3.32, s. 2H; 3.41, ζ 2H; 3.88, m, 4 H; 4.34, q, 2H; 7.17, d, 1 H; 7.92, dd, 1 H; 8.51, d. 1H; 9.92, bs, 1H.

Example 11

N, N-bis- (2-methoxyethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl ) benzenesulfonamide

<img file="SE522809C2_D0081.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 100 mg (0.784 mmol) of bis- (2-methoxyethyl) -amine 37 mg (27.5% of theory) of N, N-bis- (2-methoxyethyl) -4-ethoxy- 3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) -benzenesulfonamide.

200 MHz 1 H-NMR (CDCl 3)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, 1 H; 7.95, dd, 1 H; 8.51, d. 1H; 9.9, bs, 1H.

522 809

Example 12

N- (3-isoxazolyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonamide

<img file="SE522809C2_D0082.tif" />

<img file="SE522809C2_D0083.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 70 mg (0.784 mmol) 3-aminoisoxazole 20 mg (17.2% of theory) N- (3isoxazolyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4 -dihydro-imidazo [5,1] [1,2,4] triazin-2-yl) benzenesulfonamide.

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

Example 13

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

<img file="SE522809C2_D0084.tif" />

T JPCH O CH,

522 809

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 170 mg (0.784 mmol) of 2-t-butoxycarbonylaminomethylmorpholine 64 mg (42.2% of theory) 2- [2-ethoxy-5- (2-t-butoxycarbonylaminomethylmorpholine-4-sulfonyl) phenyl] - 5,7-dimethyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

Mass spectrum: 563 (M + H).

Example 14 io 2- [2-Ethoxy-5- (4-phenylpiperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-377-imidazo [5,1-f] [1,2,4] triazine 4-one

<img file="SE522809C2_D0085.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl ) -benzenesulfonic acid chloride and 130 mg (0.784 mmol) of 1-phenylpiperazine, 38 mg (28.3% of theory) of 2- [2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) -phenyl] -5,7-dimethyl -3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz 1 H-NMR (CDCl 3)₃): 1.62, ζ 3H; 2.72, s. 3H; 2.77, s. 3H; 3.25, m, 8H; 4.38, q, 2H; 6.92, m, 2H; 7.02, d, 1 H; 7.18-7.37, m, 3H; 7.94, dd, 1 H; 8.55, d, 1 H; 9.79, bs, 1H.

522 809

Example 15

- [2-Ethoxy-5- (3-hydroxy-3-methoxymethylpyrrolidine-1-sulfonyl) -phenyl] -5,7-dimethyl377-imidazo [5,1-f] [1,2,4] triazine -4-one

<img file="SE522809C2_D0086.tif" />

In an analogous manner, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,715 dimethyl-4-oxo-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl) benzenesulfonic acid chloride and 100 mg (0.784 mmol) of 3-hydroxy-3-methoxymethylpyrrolidine 30 mg (23.5% of theory) 2- [2-ethoxy-5- (3-hydroxy-3-methoxymethylpyrrolidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3'-imidazo [5,1-f] [1,2,4] triazin-4-one.

Mass spectrum: 478 (M + H).

Example 16

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

<img file="SE522809C2_D0087.tif" />

522 809

1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine-2- yl) -benzenesulfonic acid chloride is dissolved in 40 ml of dichloromethane and the solution is cooled to 0 ° C. After adding a DM AP spatula tip, 0.90 g (9.00 mmol) of N-methylpiperazine is added and the reaction mixture is stirred overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate 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)₃): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex, 2H; 2.29, s, 3 H; 2.51, m, 4H; 2.63, s. 3H; 3.00, t, 2H; 3.08, m, 4 H; 4.33, quart., 2H; 7.17, d, 1 H;

7.88, dd, 1 H; 8.44, d, 1 H; 9.75, s, 1 H.

Example 17

2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-37β-imidazo [5,1]] [1,2,4] triazine- 4-one-lactate

<img file="SE522809C2_D0088.tif" />

100 mg (0.211 mmol) 2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-lf] [1,2, 4] Triazin-4-one is suspended in 5 ml of ether and added with 20 mg of an 85% solution of lactic acid in water. Stir for 10 minutes at room temperature and then evaporate to dryness. The substance is triturated with ether and aspirated. There is thus obtained 110 mg (92%) of 2- [2-ethoxy-5- (4-methyl-piperazine-1sulfonyl) -phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1-lf] [ l, 2,4] triazine-4-one-lactate.

522 809

200 1 H NMR (DMSO-d 6): 0.92, 3H; 1.22, d, 3 H; 1.31, t, 3H; 1.74, m, 1 H;

2.15, s. 3H; 2.38, m, 4 H; 2.81, t, 2H; 2.91, m, 4H; 4.05, quart., 1H; 4.21, quart., 2H;

7.40, d, 1 H; 7.85, m, 2 H; 11.71, s, fold, 1H.

Example 18

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

<img file="SE522809C2_D0089.tif" />

CH₃

100 mg (0.211 mmol) 2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-37β-imidazo [5,1-lf] [1,2,4 ] triazin-4-one is suspended in 5 ml of diethyl ether, then 0.23 ml of a 1 M solution of HCl in ether is added and the mixture is stirred for 15 minutes at room temperature. The solvent is removed in vacuo. 107 mg (97%) of 2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3Himidazo [5,1] [1,2,2] are obtained. , 4] triazine-4-one hydrochloride.

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

7.95, m. 2H; 11.39, s, 1 H; 11.90, s, 1H.

522 809

Example 19

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

HRS.

'3

N.

HRS.

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

400 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.59, t, 3H; 1.88, hex., 2H; 2.42, quart.,

<img file="SE522809C2_D0090.tif" />

7.88, dd, 1 H; 8.44, d, 1 H; 9.75, s, 1 H.

522 809

Example 20

2- [2-ethoxy-5- (4-ethyl-1-piperazine-1-sulfonyl) -phenyl] -5-methyl-1-7-propyl-77-imidazo [5,1-lf] [1,2,2 4] triazine-4-one hydrochloride

<img file="SE522809C2_D0091.tif" />

0.35 g (0.712 mmol) 2- [2-ethoxy-5- (4-ethyl-piperazine-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 dichloromethane is added in such an amount that a homogeneous solution is formed. 0.8 ml of a 1 M solution of HCl in ether are added, stirred for 20 minutes at room temperature and suction filtered. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1]] [1,2] are obtained. , 4] triazine-4-one hydrochloride.

200 MHz 1 H-NMR (DMSO-d 6): 0.96, ζ 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, 2 H; 4.25, quart., 2H;

7.48, d, 1 H; 7.95, m. 2H; 11.42, s, 1 H; 12.45, s, 1H.

522 809

Example 21

2- [2-ethoxy-5- (4-methyl-1-amino-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-377-imidazo [5,1-lf] [1,2,4] triazine -4-one

<img file="SE522809C2_D0092.tif" />

In an analogous manner, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,11f] [1,2,4 ] triazin-2-yl-benzenesulfonic acid chloride and 0.03 g (0.29 mmol) of 1-amino-4-methylpiperazine 40 mg (83%) of 2- [2-ethoxy5- (4-methyl-1-amino-piperazine) 1-sulfonyl) -phenyl] -5-methyl-7-propyl-377-imidazo [5,1-f] [1,2,4] triazin-4-one.

Rf - 0.09 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)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, 4 H; 3.00, m, 2 H; 4.32, quart., 2H; 7.14, d, 1 H; 8.05, dd, 1H; 8.60, d, 1H.

522 809

Example 22

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

<img file="SE522809C2_D0093.tif" />

In an analogous manner, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]], 1,2, 4] triazin-2-yl) -benzenesulfonic acid chloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine 46 mg (91%) of 2- [2-ethoxy-5- (4-hydroxyethyl-1-amino) piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

Rf = 0.08 (dichloromethane / methanol = 19: 1)

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.59, t, 3H; 1.90, sex., 2H; 2.49, m, 6H;

2.62, s. 3H; 2.71, m, 4 H; 3.00, t, 2H; 3.55, t, 2H; 4.31, quart., 2H; 7.14, d, 1 H; 8.05, dd, 1H; 8.60, d, 1H.

522 809

Example 23

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

<img file="SE522809C2_D0094.tif" />

In an analogous manner, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2] 4] triazin-2-yl) -benzenesulfonic acid chloride and 0.043 g (0.29 mmol) of N, N-bishydroxyethylaminoethylamine 46 mg (91%) of N, N-bishydroxyethylaminoethyl-4-ethoxy-3- (5-methyl-4 -oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.53, t, 3H; 1.70, m, 2H; 1.86, sex, 2H;

2.9, m, 9H; 2.95, 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.

522 809

Example 24

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

<img file="SE522809C2_D0095.tif" />

In an analogous manner, starting from 0.4 g (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2] , 4] triazin-2-yl) -benzenesulfonic acid chloride, 390 mg triethylamine and 0.86 g (2.99 mmol) 4-dimethoxyphosphorylmethyl-piperazine trifluoroacetate 321 mg (53%) 2- [2-ethoxy-5- (4 -dimethoxyphosphorylmethyl-piperazine-120 sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1] [1,2,4] triazin-4-one.

Rf = 0.4 (dichloromethane / methanol = 20: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.60, t, 3H; 1.88, sex., 2H; 2.62, s. 3H; 2.75, m. 4H; 3.02, ζ 2H; 3.11, m, 4H; 3.70, s, 3 H; 3.75, s. 3H; 4.35, quart., 2H; 5.30, s. 2H; 7.18, d, 1 H; 7.88, dd, 1 H; 8.45, d, 1 H; 9.71, s, 1H.

522 809 PPUAP-PP · 1

................

Example 25

2- [2-ethoxy-5- (4-diethoxyphosphorylmethyl-piperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl · 3/7-imidazo [5,1] [1,2,4] triazine -4-one

<img file="SE522809C2_D0096.tif" />

In an analogous manner, starting from 0.4 g (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2] , 4] triazin-2-yl) -benzenesulfonic acid chloride and 0.86 g (3.7 mmol) of 4-diethoxyphosphorylmethyl-piperidine 366 mg (49%) of 2- [2-ethoxy-5- (4-diethoxyphosphorylmethyl-piperidine-1- sulfonyl) -phenyl] -5-methyl-7-propyl-3,7-imidazo [[5,1]] [1,2,4] triazin-4-one.

Rf = 0.4 (dichloromethane / methanol = 20: 1)

200 1 H NMR (DMSO-d 6): 0.92, 92 3H; 1.20, ζ 6H; 1.35, t, 3H; 1.75, m, 7H;

2.25, m. 2H; 2.82, t, 2H; 3.61, d. 2H; 3.95, quin., 4H; 4.21, quart., 2H; 7.38, d, 1 H;

7.87, m, 2 H; 11.70, s, 1H.

522 809 »a ··· · · · β ·· &lt;· · * ·· ··» · ·· »aaaa · ian lit a at a» aa »aaa

Example 26

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

<img file="SE522809C2_D0097.tif" />

in an analogous manner, starting from 531 mg (1.29 mmol) of 4-ethoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 393 mg (3.88 mmol) 4-hydroxypiperidine 400 mg (64%) 2- [2-ethoxy-5- (4-hydroxy-piperidine-1-sulfonyl) -phenyl] - 5-methyl-7-propyl-3,7-imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz 1 H-NMR (DMSO-cE): 0.941, ζ 3H; 1.32, ζ 3H; 1.45, m. 2H; 1.71, m, 4 H; 2.48, s, 3 H; 2.82, m, 4H; 3.11, m, 2H; 3.55, m, 1 H; 4.20, quart., 2H; 4.72, d, 1 H;

7.39, d, 1 H; 7.87, m, 2 H; 11.70, s, 1H.

522

809

Example 27

2- {2-Ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3/7-imidazo [5,1-lf] [1, 2,4] triazine-4-one

<img file="SE522809C2_D0098.tif" />

in an analogous manner, starting from 411 mg (1 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 391 mg (3 mmol) of 4-hydroxyethylpiperazine 380 mg (75%) of 2- {2-ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one

Rf = 0.198 (dichloromethane / methanol - 95: 5)

200 MHz ^l1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.60, m, 7H; 3.00, ζ 2H; 3.10, m, 4 H; 3.60, t, 2H; 4.36, quart., 2H; 7.18, d, 1 H; 7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

Example 28

2- {2-Ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3/7-imidazo [5,1-lf] [1 , 2,4] triazine-4-one hydrochloride

<img file="SE522809C2_D0099.tif" />

200 mg (0.39 mmol) 2- {2-ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} 5-methyl-7-propyl-3,7-imidazo [ 5,11f] [1,2,4] triazin-4-one is suspended in ether, added with 2 ml of a 1 M solution of HCl in ether and stirred for 20 minutes at room temperature. After removal of the solvent, 209 mg (100%) of 2- {2-ethoxy · 5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl- 3/7-imidazo 2 O [5,1] [1,2,4] triazin-4-one hydrochloride

200 MHz 1 H-NMR (DMSO-d 6): 0.96, t, 3H; 1.35, t, 3H; 1.70, sex., 2H; 2.59, s. 3H; 2.85, 2H; 2.99, t, 2H; 3.18, m, 4H; 3.59, d. 2H; 3.75, m, 4 H; 4.25, quart., 2H; 7.49 d, 1 H; 7.95, m. 2H; 10.62, s, 1 H; 12.31, s, 1H.

522 809

<img file="SE522809C2_D0100.tif" />

Example 29

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

<img file="SE522809C2_D0101.tif" />

in an analogous manner, starting from 150 mg (0.37 mmol) of 4-ethoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 158 mg (1.09 mmol) of 4- (3-hydroxypropyl) -piperazine 167 mg (83%)

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

R_f= 0.52 (dichloromethane / methanol = 10: 1)

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.61, t, 3H; 1.70, m, 5; 2.62, m, 8H; 3.00, t, 2H; 3.10, m, 4 H; 3.72, t, 2H; 4.36, quart., 2H; 7.18, d, 1 H; 7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

Example 30

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

<img file="SE522809C2_D0102.tif" />

in an analogous manner, starting from 420 mg (1.02 mmol) (1 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1 -f] ] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 300 mg (3 mmol) allylhydroxyethylamine 400 mg (82%) N-allyl4-ethoxy-N- (2-hydroxyethyl) -3- (5 -methyl-4-ozo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

Rf = 0.345 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.61, t, 3H; 1.90, m, 2H; 2.22, s, fold, 1H;

2.62, s. 3H; 2.99, 2H; 3.31, t, 2H; 3.78, t, 2H; 3.92, d. 2H; 4.37, quart., 2H; 5.23, m, 2 H; 5.71, m, 1 H; 7.15, d, 1 H; 7.98, dd, 1 H; 8.56, d. 1H; 9.66, s, 1H.

522 809

Example 31

N-ethyl-4-ethoxy-N- (2-hydroxy-ethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine-2-yl) benzenesulfonamide

O

H, C

<img file="SE522809C2_D0103.tif" />

O = S = O CH,

<img file="SE522809C2_D0104.tif" />

analogously to 411 mg (1.0 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1 -f] [1,2 , 4] triazin-2-yl) -benzenesulfonic acid chloride and 267 mg (3 mmol) of ethylhydroxyethylamine 325 mg (70%) of N-ethyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4- ozo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

Rf = 0.29 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.20, t, 3H; 1.61, t, 3H; 1.88, sex., 2H;

<img file="SE522809C2_D0105.tif" />

522 809

Example 32

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

<img file="SE522809C2_D0106.tif" />

<img file="SE522809C2_D0107.tif" />

in an analogous manner, starting from 400 mg (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-lf] [1,2, 4] triazin-2-yl) -benzenesulfonic acid chloride and 210 mg (2.92 mmol) diethylamine 398 mg (89%) N, N-diethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3 , 4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) benzenesulfonamide.

R_f = 0.49 (dichloromethane / methanol = 20: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.20, t, 6H; 1.49, t, 1.61, t, 3H; 1.88, sex., 2H; 2.30, s, fold, 1H; 2.62, s. 3H; 2.99, 2H; 3.32, m. 4H; 3.78, t, 2H; 3.80, m, 2 H; 4.37, quart., 2H; 7.15, d, 1 H; 7.98, dd, 1 H; 8.56, d. 1H; 9.70, s, 1H.

522 809

Example 33

N- (2-methoxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4 -ethoxy-bensensulfonsyraamid

<img file="SE522809C2_D0108.tif" />

<img file="SE522809C2_D0109.tif" />

in an analogous manner, starting from 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 680 mg (9 mmol) of 2-methoxyethylamine 900 mg (67%) of N- (2-methoxyethyl) -3- (5-methyl-4-oxo-7-propyl-3, 4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-etoxibensensulfonsyraamid.

R_t- = 0.25 (dichloromethane / methanol = 95: 5)

400 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.58, t, 3H; 1.88, sex., 2H; 2.62, s. 3H;

3.01, t, 2H; 3.18, quart., 2H; 3.30, s, 3 H; 3.45, t, 2H; 4.32, quart., 2H; 5.12, t, 1 H; 7.13, d, 1 H; 7.97, dd, 1 H; 8.53, d. 1H; 9.82, s, 1 H.

522 809 • ·

Example 34

N- (2-N, N-dimethylethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazine-2- yl) -4-ethoxy-bensensulfonsyraamid

<img file="SE522809C2_D0110.tif" />

in an analogous manner, starting from 210 mg (0.49 mmol) of 4-ethoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 130 mg (9 mmol) 2-N, N-dimethylethylamine 150 mg (59%) N- (2-N, N15 dimethylethyl) -3- (5-methyl-4-oxo -7-propyl-3,4-dihydro-imidazo [5,1] [1,2,4] -triazin-2-yl) -4-ethoxy-benzenesulfonic acid amide.

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.62, m, 4H; 1.88, sex_:, 2H; 2.11, s, 6H;

2.39, 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]) - 3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) -4-ethoxy-bensensulfonsyraamid

<img file="SE522809C2_D0111.tif" />

522 809 in an analogous manner to give 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,2 , 4] triazin-2-yl) -benzenesulfonic acid chloride and 1.3 g (9 mmol) of 3- (1-morpholino) -propylamine 1.38 g (88%) of N- [3- (1-morpholino) propyl] - 3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4etoxi-bensensulfonsyraamid.

Rf = 0.23 (dichloromethane / methanol = 95: 5)

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

Example 36

N- {3- [1- (4-methyl) piperazino] -propyl} -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4 ] triazine-2-yl) -4-ethoxy-bensensulfonsyraamid

<img file="SE522809C2_D0112.tif" />

in an analogous manner, starting from 0.04 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 0.05 g (0.29 mmol) of 3- [1- (4-methyl-) piperazino] -propylamine 0.04 g (77%) of N- {3- [1 - (4-methyl) piperazino] -propyl} -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) -4-ethoxy-benzenesulfonic acid amide Rf = 0.11 (dichloromethane / methanol - 95: 5)

522 809

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.55, t, 3H; 1.68, m, 2H; 1.88, sex., 2H;

2.27, s, 3 H; 2.45, m, 8H; 2.62, s, 3H, 2.98, m, 3H; 3.10, t, 2H; 3.46, s. 1H; 4.30, quart., 2H; 7.13, d, 1 H; 7.97, dd, 1 H; 8.53, d, 1 H.

Example 37

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

<img file="SE522809C2_D0113.tif" />

in an analogous manner, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 40 mg (0.29 mmol) of 4-methoxyethylpiperazine 50 mg (99%) of 2- {2-ethoxy-5- [4- (2-methoxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1]] [1,2,4] triazin-4-one

Rf = 0.27 (dichloromethane / methanol = 95: 5)

200 MHz ^l1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.60, m, 9H; 2.97, ζ 2H; 3.10, m, 4 H; 3.60, s. 3H; 3.46, t, 2H; 4.36, quail., 2H; 7.18, d, 1 H; 7.89_:dd, 1H; 8.47, d, 1 H; 9.71, s, 1H.

<img file="SE522809C2_D0114.tif" />

522 809

Example 38

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

<img file="SE522809C2_D0115.tif" />

in an analogous manner, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 50 mg (0.29 mmol) of 4- (2-N, N-dimethyl) -ethylpiperazine 50 mg (99%) of 2- {2-ethoxy-5- [4- (2 -N, N-dimethyl-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-720-propyl-377-imidazo [5,1-f] [1,2,4] triazin-4-one R_t- = 0.11 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 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, 4 H; 4.36, quart., 2H;

7.18, d, 1 H; 7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

Example 39

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

<img file="SE522809C2_D0116.tif" />

in an analogous manner, starting from 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 130 mg (0.73 mmol) of 4- (3-N, N-dimethyl) -propylpiperazine 72 mg (54%)

2- {2-Ethoxy-5- [4- (3-N, N-dimethyl-propyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-720-propyl-377-imidazo [5,1]] [ 1,2,4] triazin-4-one Rf = 0.08 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.61, t, 3H; 1.87, sex, 3H; 2.20, s. 6H;

2.25, m. 2H; 2.38, 2H; 2.52, m, 4H; 2.63, s. 3H; 2.99, m, 6H; 4.33, quart., 2H;

7.18, d, 1 H; 7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

Example 40

2- [2-Ethoxy-5- (4-dioxolano-piperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3-ylimidazo [5,1-lf] [1,2,4] triazine-4 -one

<img file="SE522809C2_D0117.tif" />

in an analogous manner, starting from 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2, 4] triazin-2-yl) -benzenesulfonic acid chloride and 100 mg (0.73 mmol) of 4-dioxolanopiperidine 111 mg (88%) of 2- [2-ethoxy-5- (4-dioxolanopiperidine-1-sulfonyl) -phenyl] -5 methyl-7-propyl-3 // - imidazo [5,1-f] [l, 2,4] triazin-4-one.

200 MHz Ή-NMR (CDCl 3₃): 1.02, ζ 3H; 1.61, t, 3H; 1.80, m, 6H; 2.63, s. 3H; 2.99, t, 2H; 3.20, m, 4 H; 3.90, s. 4H; 4.33, quart., 2H; 7.18, d, 1 H; 7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

100

Example 41

2- [2-ethoxy-5- (4- (5-methyl-4-ftuOxankarbonyl) -piperazine-l-sulfonyl) -phenyl] -5-methyl-7-propyl-3 // - imidazo [5, lf] [l , 2,4] triazine-4-one

<img file="SE522809C2_D0118.tif" />

410 mg (1.0 mmol) 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazine-2 -yl) -benzenesulfonic acid 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 trifluoroacetate and 400 mg of triethylamine are added and the reaction mixture is stirred overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution, 1 M hydrochloric acid and with water, then dried over sodium sulphate 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)₃): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex., 2H; 2.25, s. 3H; 2.63, s, 3 H; 3.00, t, 2H; 3.20, m, 4 H; 3.90, m, 2 H; 4.02, m, 2H; 4.33, quart., 2H;

7.19, d, 1 H; 7.89, dd, 1 H; 8.48, d, 1 H; 9.57, s, 1 H.

522 809

101

Example 42

2- {2-ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1]] [1,2,4] triazine- 4-one

<img file="SE522809C2_D0119.tif" />

in an analogous manner, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 40 mg (0.29 mmol) of N-acetylpiperazine 9 mg (18%) of 2- {2-ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -5- methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

Rf = 0.34 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.05, s. 3H;

2.63, s. 3H; 3.00, m, 6H; 3.59, m, 2 H; 3.72, m. 2H; 4.33, quart., 2H; 7.18, d, 1 H;

7.89, dd, 1 H; 8.47, d, 1 H; 9.71, s, 1H.

522 809

Example 43

2- {2-ethoxy-5- [4-formyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3-imidazo [5,1-f] [1,2,4] triazine -4-one

102

O '' Η.

H, C

<img file="SE522809C2_D0120.tif" />

in an analogous manner, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2, 4] triazin-2-yl) -benzenesulfonic acid chloride and 30 mg (0.29 mmol) of N-formylpiperazine 35 mg (73%) of 2- {2-ethoxy-5- [4-formyl-piperazine-1-sulfonyl] -phenyl} - 5-methyl-7-propyl-3,7-imidazo [5,1] [1,2,4] triazin-4-one.

Rf = 0.29 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.61, t, 3H; 1.87, sex, 3H; 2.05, s. 3H;

<img file="SE522809C2_D0121.tif" />

522 809

103

Example 44

2- [2-ethoxy-5- (3-butylsydononimine) -1-sulfonyl] -phenyl] -5-methyl-7-propyl-3Himidazo [5,1]] [1,2,4] triazin-4-one

HRS.

110 mg (0.6 mmol) of 3-butylsydnonimine hydrochloride is dissolved in 2.5 ml of pyridine and the solution is cooled to 0 ° C. 210 mg (0.5 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazine-2- yl) benzenesulfonic acid chloride and the reaction mixture is stirred for 2 hours at 0 ° C and overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed with water, dried over sodium sulphate and the solvent is removed in vacuo. Chromatography (dichloromethane / methanol) gives 16 mg (6%) of 2- [2-ethoxy-5- (3-butylsydnonimine) -1-sulfonyl) -phenyl] -5-methyl-7-propyl-3 / 7- imidazo [5, lf] [l, 2,4] triazin-4-one.

Rf = 0.42 (dichloromethane / methanol = 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, 2ζ 6H; 1.47, sex., 2H; 1.55, ζ 3H; 1.88, m, 2 H;

<img file="SE522809C2_D0122.tif" />

7.56, s. 1H; 7.98, dd, 1 H; 8.58, d. 1H; 9.79, s, fold, 1H.

522 809

104

Example 45

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

<img file="SE522809C2_D0123.tif" />

0.85 g (2 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazine-2- yl) -benzenesulfonic acid chloride is dissolved in 20 ml of dichloromethane and the solution is cooled to 0 ° C. After the addition of a spatula tip DMAP, 0.60 g (6.00 mmol) of N-methylpiperazine are added and the reaction mixture is stirred overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Crystallization from ether gives 0.80 g (77%) of a colorless solid.

Rf = 0.233 (dichloromethane / methanol - 95: 5)

200 MHz 1 H-NMR (CDCl 3)₃): 1.00, ζ 3H; 1.15, t, 3H; 1.87, hex., 2H; 1.99, hex., 2H; 2.30, s, 3 H; 2.52, m, 4H; 2.62, s. 3H; 2.99, t, 2H; 3.10, m, 4 H; 4.21, t, 2H; 7.17, d, 1 H; 7.87, dd, 1 H; 8.48, d, 1 H; 9.70, s, 1H.

522 809

105

Example 46

5-Methyl-2- [5- (4-methyl-piperazine-1-sulfonyl) -2-propoxy-phenyl] -7-propyl-3Himidazo [5,1]] [1,2,4] triazin-4-one hydrochloride

<img file="SE522809C2_D0124.tif" />

mg (0.045 mmol) 5-methyl-2- [5- (4-methyl-piperazine-1-sulfonyl) -2-propoxyphenyl] 7-propyl-377-imidazo [5,1] [1,2,4] triazin-4-one is dissolved in 2 ml of ether and 1 ml of dichloromethane and then 0.1 ml of a 1 M solution of HCl in ether is added. The precipitate formed is filtered off with suction after 20 minutes and dried.

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 0.95, ζ 3H; 1.75, m. 2H; 2.56, s. 3H; 2.75, m. 4H; 2.97, ζ 2H; 3.15, m, 2 H; 3.44, m, 2 H; 3.81, m. 2H; 4.15, t, 2H; 7.47, d, 1 H; 7.95, m. 2H; 11.12, s, 1 H; 12.22, s, 1H.

522 809

106

Example 47

2- [5- (4-hydroxypiperidine-l-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3 / 7imidazo [5, lf] [l, 2,4] triazine-4-one

<img file="SE522809C2_D0125.tif" />

in an analogous manner, starting from 850 mg (2 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 610 mg (6 mmol) of 4-hydroxypiperidine 736 mg (75%) of 2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl- 7-propyl-3 // - imidazo [5, lf] [l, 2,4] triazin-4-one.

Rf = 0.07 (dichloromethane / methanol = 95: 5)

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.16, t, 3H; 1.80, m, 9H; 2.65, s. 3H; 3.00, m, 4 H; 3.32, m. 2H; 3.85, m, 1 H; 4.22, t, 2H; 7.17, d, 1 H; 7.89, dd, 1 H; 8.50, d, 1 H; 11.70, s, 1H.

522 809

107

Example 48

2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-37H-imidazo [5,1]] [1,2,4] triazin-4-one

<img file="SE522809C2_D0126.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 35 mg (0.3 mmol) of 4-hydroxymethylpiperidine 41 mg (82%) of 2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl -7-propyl-3 H -imidazo [5,1] [1,2,4] triazin-4-one.

Rf = 0.52 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3₃): 1.001, ζ 3H; 1.16, t, 3H; 1.60, m. 4H; 1.82, m, 5H; 2.31, 2H; 2.62, s. 3H; 2.98, t, 2H; 3.48, d. 2H; 3.85, d. 2H; 4.21, ζ 2H; 7.17, d, 1H 7.88, dd, 1H; 8.45, d, 1 H; 9.71, s, 1H.

522 809

108

Example 49

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

HRS.

O = S =

NOH is obtained in an analogous manner starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-b] [1, 2,4] triazin-2-yl) -benzenesulfonic acid chloride and 39 mg (0.3 mmol) 4-hydroxyethylpiperazine 50 mg (96%) 2- {5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -2 -propoxy-phenyl} -5-methyl-7-propyl-3H-imidazo [5,1] [1,2,4] triazin-4-one.

Rf = 0.43 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.15, t, 3H; 1.88, m, 2 H; 2.00, m, 2H;

<img file="SE522809C2_D0127.tif" />

522 809

109

Example 50

N- (l, l-dioxotetrahydro-la⁶-thiophen-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxy -bensensulfbnsyraamid

<img file="SE522809C2_D0128.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2] 4] triazin-2-yl) -benzenesulfonic acid chloride and 41 mg (0.3 mmol) of 2-aminosulfolane 8 mg (14%) of N- (1,1-dioxotetrahydro⁶thiophene-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4 -propoxy-bensensulfonsyraamid

Rf = 0.49 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.15, t, 3H; 1.85, m. 2H; 1.99, m. 2H; 2.30, m, 1 H; 2.50, m. 1H; 2.62, s. 3H; 2.95, m, 4H; 3.21, m, 1 H; 4.20, m, 3 H; 5.98, s. 1H; 7.18, d, 1 H; 7.98, dd, 1 H; 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]] [1,2,4] triazin-2-yl) -4-propoxy-bensensulfonsyraamid

522 809

110

<img file="SE522809C2_D0129.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 31 mg (0.3 mmol) of 1,1,4-trimethyldiaminoethane 39 mg (79%) of N- (2-dimethylaminoethyl) -N-methyl-3- (5- methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxy-bensensulfonsyraamid

R_f = 0.28 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.15, t, 3H; 1.88, m, 2 H; 2.01, m. 2H;

2.25, s. 6H; 2.50, 2H; 2.62, s. 3H; 2.82, s. 3H; 3.01, t, 2H; 3.18, ζ 2H; 4.21, ζ 2H;

7.16, d, 1 H; 7.91, dd, 1 H; 8.50, d, 1 H; 9.70, s, 1H.

Example 52

- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -N- (3 morpholine-4- yl-propyl) -4-propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0130.tif" />

• · * · in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1 , 2,4] triazin-2-yl) -benzenesulfonic acid chloride and 43 mg (0.3 mmol) of 1- (3-aminopropyl) -morpholine 52 mg (97%) of 3- (5-methyl

4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] -triazin-2-yl) -N- (3-morpholin-4-yl-propyl) - 4-propoxy-benzenesulfonic acid amide Rf = 0.33 (dichloromethane / methanol = 9: 1)

522 809

111 io

200 MHz Ή-NMR (CDCl 3₃): 1.01, ζ 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, 1 H; 7.96, dd, 1 H; 8.55, d, 1 H; 9.85, s, 1 H.

Example 53

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

<img file="SE522809C2_D0131.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 32 mg (0.3 mmol) of bishydroxyethylamine 34 mg (69%) of N, N-bis- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7- propyl-3,4-dihydro-imidazo [5, l-fJ [l, 2,4] triazine-2-yl) -4propoxi-bensensulfonsyraamid

R_f - 0.36 (dichloromethane / methanol = 9: 1)

522 809

112

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.15, t, 3H; 1.85, m. 2H; 1.97, m, 2H;

2.60, s. 3H; 2.98, ζ 2H; 3.33, t, 4H; 3.87, ζ 4H; 4.20, t, 2H; 7.15, d, 1 H; 7.92, dd, 1 H; 8.49, d, 1 H; 9.85, s, 1 H.

Example 54

N- (3-hydroxybenzyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl) -4 -propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0132.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1 -f] [1,2 , 4] triazin-2-yl) -benzenesulfonic acid chloride and 37 mg (0.3 mmol) 3-hydroxybenzylamine 4 mg (8%) N- (3-hydroxybenzyl) -3- (5-methyl-4-oxo-7- propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) 4-propoxy-bensensulfonsyraamid

Rf = 0.43 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.13, t, 3H; 1.83, m. 2H; 1.96, m, 2 H; 2.59, s. 3H; 2.96, t, 2H; 4.16, m, 4 H; 5.05, t, 1H; 6.52, s. 1H; 6.70, m, 2 H; 7.06, m, 2H; 7.93, dd, 1 H; 8.41, d, 1 H; 9.77, s, 1H.

522 809

113 ι

Example 55

N-ethyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2- yl) -4-propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0133.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 27 mg (0.3 mmol) ethylhydroxyethylamine 18 mg (38%) N-ethyl-N- (2hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl- 3,4-Dihydro-imidazo [5,1-[[1,2,4] -triazin-2-yl) -4-propoxy-benzenesulfonic acid amide

Rf = 0.48 (dichloromethane / methanol - 9: 1)

200 MHz Ή-NMR (CDCl 3₃): 1.01, t, 3H; 1.15, 2h, 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 quartz, 2H; 7.15, d, 1 H; 7.95, dd, 1 H; 8.55, d, 1 H; 9.73, s, 1 H.

522 809

114

Example 56

N- (3-ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, l-fj [l, 2,4] triazine-2-yl) - 4-propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0134.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 31 mg (0.3 mmol) 3-ethoxypropylamine 47 mg (96%) N- (3-ethoxypropyl) -3 (5-methyl-4-oxo-7-propyl-3 , 4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxibensensulfonsyraamid

R_f = 0.60 (dichloromethane / methanol = 9: 1)

200 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, 4 H; 4.20, ζ 2H; 5.52, m, 1H; 7.15, d, 1H; 7.98, dd, 1H; 8.55, d, 1H; 9.85, s, 1H.

522 809

115

Example 57

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

<img file="SE522809C2_D0135.tif" />

in an analogous manner, starting from 212 mg (0.5 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2] , 4] triazin-2-yl) -benzenesulfonic acid chloride and 152 mg (1.5 mmol) 4-hydroxypiperidine 125 mg (50%) 2- [5 (4-hydroxypiperidine-1-sulfonyl) -2-propoxy-phenyl] - 5-methyl-7-propyl-3 H -imidazo [5,1-lf] [1,2,4] triazin-4-one

Rf = 0.07 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.05, ζ 3H; 1.18, t, 3H; 1.98, m, 8H; 2.71, s, 3 H; 3.10, m, 2 H; 3.28, m, 4 H; 3.88, m, 1 H; 4.28, t, 2H; 7.21, d, 1 H; 7.97, dd, 1 H; 8.45, d, 1 H; 10.45, s, 1H.

522 809

116

Example 58

3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-4-propoxy-n pyridine-4-yl-bensensulfonsyraamid

<img file="SE522809C2_D0136.tif" />

in an analogous manner, starting from 85 mg (0.2 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 56 mg (0.6 mmol) of 4-aminopyridine after refluxing for 18 hours in 1 ml of THF 24 mg (25%) of 3- (5-methyl-4-oxo-7-propyl -3,4-dihydro-imidazo [5,1] [1,2,4] triazin-2-yl) -4-propoxy-N-pyridin-4-yl-benzenesulfonic acid amide Rf = 0.13 (dichloromethane / methanol = 9: 1)

2 00 MHz 1 H-NMR (CDCl 3₃ + CD₃OD): 1.01, t, 3H; 1.09, t, 3H; 1.90, m, 4H; 2.60, s. 3H; 2.99, 2H; 4.16, 2H; 7.05, d, 2H; 7.15, d, 1 H; 7.88, d. 2H; 8.05, dd, 1H; 8.41, d, 1H.

522 809

117

Example 59

N, N-diethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxy-bensensulfonsyraamid io

<img file="SE522809C2_D0137.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 22 mg (0.6 mmol) diethylamine 42 mg (92%) N, N-diethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxy-bensensulfonsyraamid

Rf = 0.64 (dichloromethane / methanol = 9: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.18, 2h, 9H; 1.92, 2 hex., 4H; 2.62, s. 3H;

3.00, ζ 2H; 3.29, quart., 4H; 4.21, t, 2H; 7.13, d, 1 H; 7.93, dd, 1 H; 8.51, d. 1H; 9.85 s, 1H.

522 809

118

Example 60 1- [3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonyl] piperidine-4-carboxylic acid

<img file="SE522809C2_D0138.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2] 4] triazin-2-yl) -benzenesulfonic acid 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 21 mg (41%) of 1- [ 3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] - [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonyl] piperidine-4-carboxylic acid.

R_f = 0.28 (dichloromethane / methanol = 9: 1)

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

522 809

119

Example 61

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

<img file="SE522809C2_D0139.tif" />

analogously, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2 , 4] triazin-2-yl) -benzenesulfonic acid chloride and 26 mg (0.3 mmol) morpholine 34 mg (71%) 5-methyl-2- [5- (morpholine-4sulfonyl) -2-propoxy-phenyl] - 7-propyl-3 H -imidazo [5,1-b] [1,2,4] triazin-4-one.

Rf = 0.64 (dichloromethane / methanol = 9: 1)

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.01, ζ 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, 1 H; 7.89, dd, 1 H; 8.48, d, 1 H; 9.78, s, 1 H.

Example 62

N- (2-hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazine-2- yl) -4-propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0140.tif" />

ΌΗ ^{522 809} PRUOuffi ·:

120 in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-b] [1,2, 4] triazin-2-yl) -benzenesulfonic acid chloride and 23 mg (0.63 mmol) of methylhydroxyethylamine 25 mg (54%) of N- (2-hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7 -propyl-3,4-dihydro-imidazo [5,1] [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonic acid amide.

Rf = 0.53 (dichloromethane / methanol = 9: 1) io

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.15, t, 3H; 1.82, m, 2H; 1.99, hex., 2H;

2.40, s, fold, 1H; 2.62, s. 3H; 2.89, s. 3H; 2.99, 2H; 3.21, 2H; 3.80, s, fold, 2H; 4.21, ζ 2H; 7.16, d, 1 H; 7.92, dd, 1 H; 8.50, d, 1 H; 9.79, s, 1 H.

Example 63

N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) - 4-propoxy-N-propyl-bensensulfonsyraamid

<img file="SE522809C2_D0141.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] (1,2,4 ] triazin-2-yl) -benzenesulfonic acid chloride and 31 mg (0.6 mmol) of propylhydroxyethylamine 20 mg (40%) of N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3, 4-Dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxy-N-propyl-benzenesulfonic acid amide.

Rf = 0.52 (dichloromethane / methanol = 9: 1)

522 809

200 MHz Ή-NMR (CDCl 3₃): 0.90, ζ 3H; 1.01, t, 3H; 1.15, t, 3H; 1.52, m, 2H; 1.88,

121

<img file="SE522809C2_D0142.tif" />

<img file="SE522809C2_D0143.tif" />

<img file="SE522809C2_D0144.tif" />

Example 64

N- [2- (3,4-dimethoxy-phenyl) ethyl] -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2] , 4] triazin-2-yl) -4-propoxy-bensensulfonsyraamid

<img file="SE522809C2_D0145.tif" />

In an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4 ] triazin-2-yl) -benzenesulfonic acid chloride and 59 mg (0.3 mmol) of N-methyl-3,4-dimethoxyphenylethylamine 45 mg (78%) of N- [2- (3,4-dimethoxyphenyl) -ethyl] -N -methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide.

R_f - 0.35 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 0.90, t, 3H; 1.07, t, 3H; 1.78, m, 2H; 1.92, m, 2H;

<img file="SE522809C2_D0146.tif" />

<img file="SE522809C2_D0147.tif" />

522 809

122

Example 65

N-allyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazin-2-yl) -4-propoxibensensulfbnsyraamid

<img file="SE522809C2_D0148.tif" />

In an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 31 mg (0.3 mmol) allylhydroxyethylamine 34 mg (70%) N-allyl-N- (2hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl- 3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide.

R_f = 0.52 (dichloromethane / methanol = 9: 1)

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

522 809

123

Example 66

N-allyl-N-cyclopentyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxibensensulfonsyraamid

<img file="SE522809C2_D0149.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 38 mg (0.3 mmol) of allyl cyclopentylamine 33 mg (64%) of N-allyl-N-cyclopentyl-3- (5-methyl-4-oxo-7-propyl) 3,4-Dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide.

Rf = 0.43 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, ζ 3H; 1.15, t, 3H; 1.53, m, 9H; 2.00, m, 4H;

2.63, s. 3H; 3.00, t, 2H; 3.80, m, 2 H; 4.21, t, 2H; 5.20, m, 2 H; 5.88, m, 1 H; 7.12, d, 1 H; 7.95, dd, 1 H; 8.55, d, 1 H; 9.75, s, 1 H.

522 809

124

<img file="SE522809C2_D0150.tif" />

Example 67

N-allyl-N-ethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide

<img file="SE522809C2_D0151.tif" />

in an analogous manner, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] ] triazin-2-yl) -benzenesulfonic acid chloride and 26 mg (0.3 mmol) of allylethylamine 30 mg (64%) of N-allyl-N-ethyl-3- (5-methyl4-oxo-7-propyl-3,4 -dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) -4-propoxibensensulfonsyraamid.

Rf = 0.44 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.15, t, 6H; 1.89, m, 2H; 2.01, m. 2H;

2.63, s. 3H; 3.00, ζ 2H; 3.27, quart., 2H; 3.87, d, 2H; 4.23, 2H; 5.20, m, 2 H; 5.72, m, 1 H; 7.15, d, 1 H; 7.95, dd, 1 H; 8.55, d, 1 H; 9.80, s, 1H.

522 809

Example 68

125

2- [2-ethoxy-4-methoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3-imidazo [5,1-lf] [1,2,4] triazine -4-one

HRS.

= S = O i

CH.

N

IN

CH, mg (0.045 mmol) 4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride is dissolved in 0.5 ml of dichloromethane, then a spatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine is added and the reaction mixture is then stirred overnight at room temperature. After purification on silica gel, 12.8 mg (55%) of 2- [2-ethoxy-4-methoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3/7-imidazo are obtained. [5,1 -f] [1,2,4] triazin-4-one.

Rf = 0.22 (dichloromethane / methanol = 20: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 0.94, t, 3H; 1.55, t, 3H; 1.80, m. 2H; 2.24, s. 3H; 2.42,

<img file="SE522809C2_D0152.tif" />

8.57, s. 1H; 9.54, s, 1 H.

522 809

126

Example 69

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -4-methoxy-phenyl} -5-methyl-7-propyl-3,7-imidazo [5,1] [1,2,4] triazin-4-one

HRS.

O = S = O

j.

In an analogous manner, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5 (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,2], 4] triazin-2-yl) -benzenesulfonic acid chloride and 18 mg (0.14 mmol) of 4-hydroxyethylpiperazine 11 mg (46%) of 2- {2 ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl ] -4-methoxyphenyl} -5-methyl-7-propyl 3 H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.3 4 (dichloromethane / methanol = 15: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 0.94, ζ 3H; 1.55, t, 3H; 1.80, m, 3H; 2.52, m, 9H;

<img file="SE522809C2_D0153.tif" />

s, 1H; 9.55, s, 1 H.

522 809

127

Example 70

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

<img file="SE522809C2_D0154.tif" />

In an analogous manner, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5 (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1, 2,4] triazin-2-yl) -benzenesulfonic acid chloride and 12 mg (0.14 mmol) ethylhydroxyethylamine 8 mg (34%) 4-ethoxyN-ethyl-N- (2-hydroxyethyl) -2-methoxy-5- (5 -methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonic acid amide

R_f= 0.45 (dichloromethane / methanol = 15: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, t, 3H; 1.18, t, 3H; 1.61, t, 2H; 1.88, m, 2 H; 2.3 s, broad, 1H; 2.65, s. 3H; 3.00, ζ 2H; 3.38, quart., 2H; 3.45, t, 2H; 3.78, m, 2H, 4.01 s.

s, 3H; 4.20, quart., 2H; 6.58, s. 1H; 8.67, s, 1 H; 9.61, s, 1H.

522 809

128

Example 71

4-ethoxy-N- (4-ethoxyphenyl) -2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, lf] [l, 2,4] triazine 2-yl) -bensensulfonsyraamid

<img file="SE522809C2_D0155.tif" />

In an analogous manner, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5 (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1, 2,4] triazin-2-yl) -benzenesulfonic acid 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, lf] [l, 2,4] triazine-2-yl) -bensensulfonsyraamid

Rf = 0.36 (dichloromethane / methanol = 20: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.33, t, 3H; 1.59, t, 3H; 1.86, hex., 2H;

2.62, s. 3H; 3.02, ζ 2H; 3.92, quart., 2H; 4.11, s, 3 H; 4.31, quart., 2H, 6.58, s, 1H; 6.72, d, 2H; 6.88, s, fold, 1H; 6.99, d, 2H; 8.50, s. 1H; 9.59, s, 1 H.

522 809

129

Example 72

4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine- 2-yl) bensensulfonsyraamid

<img file="SE522809C2_D0156.tif" />

0.64 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazine 2-yl) -benzulfonic acid chloride is dissolved in 20 ml of dichloromethane and the solution is cooled to 0 ° C. After the addition of a spatula tip to dimethylaminopyridine, 0.40 g (4.50 mmol) of 2- (ethylamino) -ethanol are added and the reaction mixture is stirred overnight at room temperature. It is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed in vacuo. Chromatography (dichloromethane / methanol = 95: 5) gives 0.454 g (63%) of a colorless solid.

200 MHz ¹ 1 H-NMR (CDCl 3)₃): 1.02, ζ 3H; 1.20, t, 3H; 1.35, t, 3H; 1.61, 3H; 1.88, sex., 2H; 2.25, s, fold, 1H; 3.01, m, 4H; 3.32, m. 4H; 3.70, m, 2 H; 3.80, m, 2 H; 4.37, quart., 2H; 7.15, d, 1 H; 7.98, dd, 1 H; 8.56, d. 1H; 9.70, s, 1H.

522 809

130

Example 73

<img file="SE522809C2_D0157.tif" />

N- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine

2-yl) -4-etoxibensensulfonsyraamid

<img file="SE522809C2_D0158.tif" />

In an analogous manner, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 21 mg (0.282 mmol) of 2-methoxyethylamine 15 mg (34%) of N- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo) [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonic acid amide

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

200 MHz 1 H-NMR (CDCl 3)₃): 0.97, t, 3H; 1.25, t, 3H; 1.53, t, 3H; 1.82, hex., 2H;

2.97, m, 4H; 3.11, m, 2H; 3.22, s. 3H; 3.39, t, 2H; 4.37, quart., 2H; 5.00, 1H; 7.17, d, 1H; 7.97, dd, 1H; 8.53, d, 1H; 9.82, s, 1H.

522 809

131 ................

Example 74

N, N-bis (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, lf] [l, 2,4] tri-azine-2- yl) -4-etoxibensensulfonsyraamid

<img file="SE522809C2_D0159.tif" />

In an analogous manner, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-415-oxo-7-propyl-3,4-dihydro-imidazo [5,1]] [1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and 38 mg (0.28 mmol) of bismethoxyethylamine 17 mg (34%) of N, N-bis- (2-methoxyethyl) -3 (5-ethyl-4-oxo-7-propyl) 3,4-dihydroimidazo [5, lf] [l, 2,4] triazine-2-yl) -4-etoxibensensulfonsyraamid

Rf = 0.34 (ethyl acetate / cyclohexane - 2: 1)

200 MHz 1 H-NMR (CDCl 3₃): 0.97, ζ 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, 4 H; 4.27, quart., 2H; 7.17, d, 1 H; 7.97, dd, 1 H; 8.53, d. 1H; 9.82, s, 1 H.

522 809

Example 75

2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl-3,7-imidazo [5,1- [[1,2,4] triazine-2 -one

132

<img file="SE522809C2_D0160.tif" />

In an analogous manner, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 460 mg (4.5 mmol) of 4-hydroxypiperidine 485 mg (66%) of 2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7 -propyl-3 // - imidazo [5, L / J [l, 2,4] triazin4-one

R_f= 0.37 (dichloromethane / methanol = 19: 1)

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

522 809

Example 76

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

133

HRS.

CH.

HO

In an analogous manner, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 33 mg (0.28 mmol) of 4-hydroxymethylpiperidine 23 mg (48%) of 2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl -3 // imidazo [5,1] [1,2,4] triazin-4-one

Rf = 0.38 (dichloromethane / methanol = 10: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 1.01, t, 3H; 1.33, t, 3H; 1.60, t, 3H; 1.80, m, 8H; 2.41,

<img file="SE522809C2_D0161.tif" />

d, 1H; 9.71, s, 1H.

522 809

134 .....* .......

Example 77

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

<img file="SE522809C2_D0162.tif" />

In an analogous manner, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [1,2,4] triazine-2 -yl) -benzenesulfonic acid chloride and 37 mg (0.28 mmol) of 4-hydroxyethylpiperazine 35 mg (71%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -phenyl} -5 ethyl-7-propyl-3/7-imidazo [5, lf] [l, 2,4] triazin-4-one.

R_f = 0.65 (dichloromethane / methanol = 10: 1)

Example 78

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

<img file="SE522809C2_D0163.tif" />

IN

CH₃

522 809

135

In an analogous manner, starting from 640 mg (1.50 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 450 mg (4.5 mmol) of 4-hydroxyethylpiperazine 495 mg (66%) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5-ethyl-7 -propyl-3H-imidazo [5,1] [1,2,4] triazin-4-one.

Rf = 0.30 (dichloromethane / methanol = 19: 1)

<img file="SE522809C2_D0164.tif" />

8.48, d, 1 H; 9.65, s, 1 H.

Example 79

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

CH.

'3

<img file="SE522809C2_D0165.tif" />

300 mg (0.61 mmol) 2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-lf] [1, 2,4] triazin-4-one is dissolved in a mixture of ether and dichloromethane and added to 2 ml of a 1 M solution of HCl in ether. After 20 minutes, the precipitated solid is filtered off with suction and dried.

200 1 H NMR (DMSO-d 6): 0.95, t, 3H; 1.32, 2ζ 6H; 1.80, sex., 2H; 2.76,

<img file="SE522809C2_D0166.tif" />

d, 1H; 7.95, m. 2H; 11.25, s, 1 H; 12.30, s, 1H.

522 809 ppijpp.p136

Example 80

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

<img file="SE522809C2_D0167.tif" />

In an analogous manner, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 650 mg (4.5 mmol) of 1- (3-aminopropyl) -morpholine 476 mg (59%) of 3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [ 5, f] [l, 2,4] triazine-2-yl) -N- (3-morpholin-4-yl-propyl) -4-ethoxy-benzene-sulfonic acid amide

Rf = 0.18 (dichloromethane / methanol = 19: 1)

200 MHz 1 H-NMR (CDCl 3)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, 1 H; 7.95, dd, 1 H; 8.55, d, 1 H; 9.82, s, 1 H.

522 809

137

Example 81

N- (2-hydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2-yl) -4 ethoxy-N-propyl-bensensulfonsyraamid

<img file="SE522809C2_D0168.tif" />

In an analogous manner, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-lf] [1,2,4] triazine -2-yl) -benzenesulfonic acid chloride and 464 mg (4.5 mmol) of propylhydroxyethylamine 600 mg (81%) of N- (2-hydroxyethyl) -3 (5-ethyl-4-oxo-7-propyl-3,4-dihydro imidazo [5, lf] [l, 2,4] triazine-2-yl) -4-ethoxy-Npropylbensensulfonsyraamid.

Rf = 0.73 (dichloromethane / methanol = 10: 1)

200 MHz 1 H-NMR (CDCl 3)₃): 0.91, ζ 3H; 1.01, t, 3H; 1.32, t, 3H; 1.62, m, 5H; 1.88, m, 2 H; 2.32, s, 1 H; 3.01, m, 4H; 3.22, m, 4 H; 3.80, m, 2 H; 4.35, t, 2H; 7.15, d. 2H;

7.95, dd, 1 H; 8.55, d, 1 H; 9.75, s, 1 H.

The sulfonamides listed in the following Tables 1, 2, 3, 4 and 6 were prepared by automated parallel synthesis from 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1]] [ 1,2,4] triazin-2-yl) -benzenesulfonic acid chloride and the corresponding amine according to one of the following three standard regulations.

The sulfonamides listed in Table 5 were prepared analogously by automated parallel synthesis from 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-δ] [1,2,1 4] triazin-2-yl) -benzenesulfonic acid chloride and the corresponding amine.

522 809 PS ;. Ί

138 ........

The purity of the final products was determined by HPLC and their characterization was done by LC-MS measurement. The content of the desired compound according to HPLCMS is given in the tables in the column "HPLC" in percent. Standard Regulation A was used for amines with acidic functionalities, Standard Regulation B for amines with neutral functionalities and Standard Regulation C for amines with additional basic functionalities.

In the structural formulas of the following Tables 1, 2, 3, 4, 5 and 6, representation of the hydrogen atoms is sometimes omitted. Nitrogen atoms with a free valence should therefore be understood as -NH residue.

Standard Regulation A: Reaction of amines with acidic functionalities

Initially, the starting material is 0.05 mmol amine, 0.042 mmol sulfonic acid chloride and 0.10 mmol Na₂CO₃ and by pipette add 0.5 ml of a mixture of THF / H₂O. After 24 hours at room temperature, 0.5 ml of 1M H is added₂SE₄solution and filtered through a two-phase cartridge filter (500 mg Extrelut (superphase) and 500 mg SiO₂, concomitant solvent acetic acid). After evaporation of the filtrate in vacuo, the product is obtained.

Standard regulation B: Reaction of amines with neutral functionalities Initially, 0.125 mmol of amine is used as the starting point, and from the Synthesizer, 0.03 mmol of sulfonic acid chloride is added by pipette as a solution in 1,2-dichloroethane. After 24 hours, the mixture is added with 0.5 ml of 1 MH₂SE₄ and filtered over a two-phase cartridge (500 mg Extrelut (over-phase) and 500 mg SiO₂, co-solvent: acetic acid). The filtrate is evaporated in vacuo.

Standard regulation C: Reaction of amines with basic functionalities Initially, 0.05 mmol of amine are used as the starting point and 0.038 mmol of sulfonic acid chloride are added by pipette as a solution in 1,2-dichloroethane and 0.05 mmol of triethylamine as a solution in 1,2- dichloroethane. After 24 hours, first add 3 ml of saturated NaHCO 3₃solution and the reaction mixture is filtered through a two-phase cartridge. After evaporation of the filtrate in vacuo, the product is obtained.

522 809 ρρί. jnn.fiS · 1 ·

139

All reactions are monitored by thin layer chromatography. In the event that after 24 hours at room temperature no complete reaction has taken place, heat for a further 12 hours at 60 ° C and then the experiment is terminated.

522 809

140

Exem- MV

<img file="SE522809C2_D0169.tif" />

522 809

141

ExemMV pel nr

Structure (g / mol) HPLC MS + H

<td> 85</td><td>o £ 2</td><td> 477,58687</td><td> 76</td><td> 478</td>

<td> 86</td><td>CH, o rw i Y^v\ 1 CH, o = s = o ^ γΝ u</td><td> 525,63147</td><td> 81</td><td> 526</td>

<td> 87</td><td>CH, 0 ΓΗ ς, ΛγΧ (V^v\ T CH, 0 = s = o 1 N</td><td> 463,55978</td><td> 65</td><td> 464</td>

522 809

142

ExemMV

<img file="SE522809C2_D0170.tif" />

522 809

143

ExemMV pel nr

Structure (g / mol) HPLC MS + H

<td> 91</td><td>CH, 0 _r., Λχ Λχ 1 1 1 aⁿσχ I CH, o = s = o</td><td> 581,6962</td><td> 76</td><td> 582</td>

<td> 92</td><td>CH, 0 &lt;~ u ζ _N\ X 1 1 1 λ^ν(V^vX I CH, o = s == o⁰ 1 X</td><td> 475,5273</td><td> 61</td><td> 476</td>

<td> 93</td><td>^{o =}v&gt; ί_χ - \ = Μ- \ o /</td><td> 421,47851</td><td> 80</td><td> 422</td>

522 809

144

ExemMV

<img file="SE522809C2_D0171.tif" />

522 809

145

Example MV pel no Structure (g / mol) HPLC MS + H

<td> 96</td><td>Q</td><td>ζ,, o = s = o 1 N HO</td><td>v 1 /,^NCH</td><td> 567,71274</td><td> 80</td><td> 568</td>

<td></td><td></td><td>ϋ 1</td><td>CH.</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>T</td><td></td><td></td><td></td>

<td> 97</td><td></td><td>Y</td><td rowspan="2">s CH</td><td> 521,64045</td><td> 94</td><td> 522</td>

<td></td><td></td><td>o = s = o 1</td><td></td><td></td><td></td>

<td></td><td>HC 'O-'^-H3C</td><td>c CH</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">CH. O Γ II</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>? fr ΛΑ / * ·</td><td></td><td></td><td></td><td></td>

<td> 98</td><td></td><td></td><td rowspan="2">s CH</td><td> 477,58687</td><td> 70</td><td> 478</td>

<td></td><td> 0</td><td>= S = o 1</td><td></td><td></td><td></td>

<td></td><td></td><td>1 r^N</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>-CH</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">HO _</td><td></td><td></td><td></td><td></td>

522 809

146

ExemMV pel nr Structure (g / mol) HPLC MS + H

<td rowspan="2"> 99</td><td colspan="2">ch. ό</td><td rowspan="2">al Az 0</td><td rowspan="2">.Ν CH</td><td rowspan="2"> 535,62391</td><td rowspan="2"> 88</td><td rowspan="2"> 536</td>

<td>Z o</td><td>o = s =</td>

<td></td><td></td><td></td><td>θ</td><td>ΟΗ,</td><td></td><td></td><td></td>

<td></td><td></td><td> %</td><td></td><td>Λ</td><td></td><td></td><td></td>

<td></td><td></td><td>IV</td><td>Ex</td><td> &lt;</td><td></td><td></td><td></td>

<td></td><td></td><td>T</td><td></td><td rowspan="2">Λ CH</td><td></td><td></td><td></td>

<td></td><td></td><td>o = s = o</td><td></td><td></td><td></td><td></td>

<td> 100</td><td></td><td> ?</td><td></td><td></td><td> 553,68565</td><td> 88</td><td> 554</td>

<td></td><td>r</td><td>r.0</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>fY</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>u</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>chl r</td><td>0 Η</td><td>Μ</td><td></td><td></td><td></td>

<td></td><td></td><td> %</td><td>? Ί</td><td>Α</td><td></td><td></td><td></td>

<td></td><td></td><td>Λ</td><td>Αζ</td><td>Q</td><td></td><td></td><td></td>

<td> 101</td><td></td><td> 9</td><td></td><td rowspan="2">Λ CH</td><td> 529,61972</td><td> 85</td><td> 530</td>

<td></td><td>5 -O</td><td colspan="2"> 0=3=0</td><td></td><td></td><td></td>

<td></td><td>XXO,</td><td> 1</td><td></td><td></td><td></td><td></td><td></td>

522 809

147

ExemMV pel nr

Structure (g / mol) HPLC MS + H

<td> 102</td><td>ζ, n</td><td>CH</td><td> 539,65856</td><td> 91</td><td> 540</td>

<td></td><td>ϋ 1</td><td></td><td></td><td></td><td></td>

<td></td><td>ϊ i¹OF</td><td>A A</td><td></td><td></td><td></td>

<td> 103</td><td>V o = s = o 1 /</td><td>s CH</td><td> 520,61209</td><td> 55</td><td> 521</td>

<td></td><td>° yc</td><td></td><td></td><td></td><td></td>

<td></td><td>CH. 0 I 1</td><td></td><td></td><td></td><td></td>

<td></td><td>AA</td><td>ό</td><td></td><td></td><td></td>

<td> 104</td><td>V o = s = o</td><td>\ CH</td><td> 502,64038</td><td> 82</td><td> 503</td>

<td></td><td>IN</td><td></td><td></td><td></td><td></td>

522 809

148

ExemMV

<img file="SE522809C2_D0172.tif" />

149

522 809

Exem- MV

<img file="SE522809C2_D0173.tif" />

522 809

150

Table 2:

Exem- MV

<img file="SE522809C2_D0174.tif" />

522 809 ·· * ·· · · · * ·· ·· ** ·· • · · · · · · · · · · · · · · · · · · · til · »♦ · * · ·» · · · · · · · ·· • · · · «« «» «» «» ·

151

<img file="SE522809C2_D0175.tif" />

522 809

152

Example MV pel no Structure (g / mol) HPLC MZ + H

<td> 114</td><td colspan="2">CH, 0 / Λ O = s = o</td><td> $</td><td> 521,6405</td><td> 95</td><td> 522</td>

<td></td><td></td><td>CH, 0 CI</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>1 i⁷</td><td>Λ T</td><td></td><td></td><td></td>

<td> 115</td><td>HO</td><td>φ o = s = o</td><td>s CH</td><td> 569,6851</td><td> 84</td><td> 570</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Γ 'CH.</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 Γ 1</td><td>CH</td><td></td><td></td><td></td>

<td></td><td></td><td>1 H AAR</td><td></td><td></td><td></td><td></td>

<td> 116</td><td>HO</td><td rowspan="2">O = S-0</td><td>s CH</td><td> 608,5486</td><td> 85</td><td> 608</td>

<td></td><td></td><td> 3</td><td></td><td></td><td></td>

<td></td><td></td><td>/ α</td><td></td><td></td><td></td><td></td>

&gt; * · «Ft ft ttfttt ·

153

Exem522 809

MV

<img file="SE522809C2_D0176.tif" />

522 809

154 pel no Structure (g / mol) HPLC MZ + H

MV

Exem-

<td> 120</td><td>CH, O _rw1 CH3 Q g - Γ)</td><td> 517,6522</td><td> 71</td><td> 518</td>

<td> 121</td><td>CH. 0_ruaa 1 1 '/,^N„ΌΑ Vo 1 ch, \ 0 — S — 0 A Cr</td><td> 561,7058</td><td> 92</td><td> 562</td>

<td> 122</td><td>ζ Xf 1 1 1 / N έΑζ 1 CHj o = s = o OA</td><td> 539,6586</td><td> 85</td><td> 540</td>

522 809

155

ExemMV

<img file="SE522809C2_D0177.tif" />

522 809

156

Exem- MV

<td colspan="2">pel nr Structure</td><td colspan="3">(g / mol) HPLC M 2 + H</td>

<td> 126</td><td>CH ⁰ ΓΗ (V^v\ 1 CH, o = s = o 9 0</td><td> 542,7057</td><td> 77</td><td> 543</td>

<td> 127</td><td>CH, Ο γη ϊ / ~ υ 1 CH, o = s = o</td><td> 502,6404</td><td> 91</td><td> 503</td>

<td> 128</td><td>CH. O_rHI CH, CH, 0 = S = 0 hrs₃C^xNX-^/^^{h &lt;}CH</td><td> 490,6292</td><td> 45</td><td> 491</td>

522 809₁₅₇

ExemMV

<img file="SE522809C2_D0178.tif" />

522 809

158

Exem- MV

<img file="SE522809C2_D0179.tif" />

522 809.

159

ExemMV

<img file="SE522809C2_D0180.tif" />

522 809

160

ExemMV

<img file="SE522809C2_D0181.tif" />

522 809

161

Example MV pel no Structure (g / mol) HPLC MZ + H

<td> 139</td><td>CH. 0 ς, λ o = s = o OH Cr</td><td>J '¹A X CH</td><td> 489,598</td><td> 85</td><td> 490</td>

<td></td><td>CH. 0 I 1</td><td></td><td></td><td></td><td></td>

<td></td><td>ΐ π</td><td>A</td><td></td><td></td><td></td>

<td></td><td>(iW</td><td>ί</td><td></td><td></td><td></td>

<td> 140</td><td>T</td><td rowspan="2">A CH</td><td> 475,5709</td><td> 83</td><td> 476</td>

<td></td><td>o = s = o 1 / A</td><td></td><td></td><td></td>

<td></td><td>HO-O</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 1 1</td><td>CH</td><td></td><td></td><td></td>

<td></td><td>1 | T</td><td></td><td></td><td></td><td></td>

<td></td><td>AAR</td><td></td><td></td><td></td><td></td>

<td> 141</td><td>V</td><td rowspan="2">A CH</td><td> 503,6251</td><td> 85</td><td> 504</td>

<td></td><td>o = s = o IN</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

, · · « « ·

522 809

162

Example no

Structure

MV (g / mol) HPLC MZ + H

142

<img file="SE522809C2_D0182.tif" />

O = S = O

143

<img file="SE522809C2_D0183.tif" />

<img file="SE522809C2_D0184.tif" />

O == S = O

OH

489,598

461,5438

539,6586

490

462

540

144

<img file="SE522809C2_D0185.tif" />

522 809

163

Structure (g / mol) HPLC MZ + H

ExemMV pel nr

<img file="SE522809C2_D0186.tif" />

<img file="SE522809C2_D0187.tif" />

<img file="SE522809C2_D0188.tif" />

522 809

164

Table 3:

Exem- MV

<td>pel nr</td><td colspan="3">Structure</td><td>(G / mol)</td><td>HPLC</td><td>Mz + H</td>

<td></td><td>ϋ 1</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ϊ A AX-</td><td>t</td><td></td><td></td><td></td><td></td>

<td></td><td>U</td><td>A</td><td></td><td></td><td></td><td></td>

<td> 148</td><td>T o = s = o 1</td><td></td><td>CH</td><td> 565,70</td><td> 38</td><td> 566</td>

<td></td><td>OH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>u</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 0</td><td>CH</td><td></td><td></td><td></td>

<td></td><td colspan="2">a o aa-</td><td>A</td><td></td><td></td><td></td>

<td> 149</td><td>A T H, C \ O = S = O V /</td><td>c</td><td>CH CH</td><td> 643,77</td><td> 85</td><td> 644</td>

<td></td><td>0 \ CH</td><td></td><td></td><td></td><td></td><td></td>

⁵²² 8θ9 „, loS • ·

MV

Structure (g / mol) HPLC Mz + H

Example no

<img file="SE522809C2_D0189.tif" />

522 809

166

Exem- MV

<img file="SE522809C2_D0190.tif" />

522 809

167

ExemMV

<img file="SE522809C2_D0191.tif" />

• · · « • « · « · • · · ·

522 809

168

ExemMV

<img file="SE522809C2_D0192.tif" />

522 809

169

ExemMV

<img file="SE522809C2_D0193.tif" />

522 809

170

ExemMV

<img file="SE522809C2_D0194.tif" />

522 809

171

MV

Exem-

<img file="SE522809C2_D0195.tif" />

522 809

172

Example MV pel no Structure (g / mol) HPLC Mz + H

<td> 164</td><td>CH. O ph I CH, 0-s = o W | X 'n'x,' * V</td><td> 501,61</td><td> 75</td><td> 502</td>

<td> 165</td><td>CH, 0 Λχ Λχ 1 1 ZN O-\ o = s = o_VJ^!CH</td><td> 491,61</td><td> 91</td><td> 492</td>

<td> 166</td><td>CH, O ru T CH, o = s = o</td><td> 477,59</td><td> 73</td><td> 478</td>

522 809

173

Example no

MV

Structure (g / mol) HPLC Mz + H

<td> 167</td><td>9 ^ »2 CHj X Ax ^{K £ rai}| CH o = s = o</td><td> 525,63</td><td> 81</td><td> 526</td>

<td> 168</td><td>ζ A / · Ear oio 1 rr^Nhr</td><td> 488,57</td><td> 70</td><td> 489</td>

522 809

174

Example no

MV

Structure (g / mol) HPLC Mz + H

<td> 169</td><td>Ν Ν V Iι I zN (Υ'ύ, T CH, o = s = o / V her</td><td> 511,60</td><td> 76</td><td> 512</td>

<td> 170</td><td>CH, 0 I CH, oh o-, , axr</td><td> 568,70</td><td> 50</td><td> 569</td>

<td> 171</td><td>ii 1 / N T CH, OH 0 — S = O</td><td> 554,67</td><td> 63</td><td> 555</td>

522 809

175

Exem- MV

<td colspan="2">pel nr Structure</td><td colspan="3">(g / mol) HPLC Mz + H</td>

<td> 172</td><td>CH, 0 ΓΗ ! Λα άΑΛ T CH, ΟΗ Ο — S = O όχτ</td><td> 582,73</td><td> 50</td><td> 583</td>

<td> 173</td><td>Λ Λ /¹0 o = s = o CUR</td><td> 637,76</td><td> 30</td><td> 638</td>

522 809

176

Exem- MV

<img file="SE522809C2_D0196.tif" />

522 809

177

Table 4:

MV

Exem-

<img file="SE522809C2_D0197.tif" />

522 809

178

Example no

MV

Structure (g / mol) HPLC Mz + H

<td> 179</td><td>T H, C</td><td>LT o = s = o</td><td>Γ in CH</td><td> 513,62</td><td> 47</td><td> 514</td>

<td></td><td></td><td>CH, 0 ϋ i</td><td>CH</td><td></td><td></td><td></td>

<td></td><td></td><td>i fr</td><td>ί</td><td></td><td></td><td></td>

<td></td><td></td><td>(W</td><td>t</td><td></td><td></td><td></td>

<td> 180</td><td></td><td>T</td><td rowspan="2">Λ</td><td> 504,66</td><td> 83</td><td> 505</td>

<td></td><td>CH</td><td>o = s = o |</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>'CH</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 L JL</td><td>CH</td><td></td><td></td><td></td>

<td></td><td></td><td>T IT '' '</td><td rowspan="2">island¹</td><td></td><td></td><td></td>

<td></td><td></td><td>AA¹</td><td></td><td></td><td></td>

<td> 181</td><td>α</td><td>φ CH, 0 — S — 0</td><td>s CH</td><td> 552,70</td><td> 83</td><td> 553</td>

522 809

179 • · • · · • »

Exem- My

<img file="SE522809C2_D0198.tif" />

522 809

180

Exem- MV

<td colspan="2">pel nr Structure</td><td colspan="3">(g / mol) HPLC Mz + H</td>

<td> 184</td><td>CH, θ ΓΗ Ϊ / Τ- άΤ-Λ Τ _Λ CH 0 = s = o / HC-N CH, CH</td><td> 504,66</td><td> 82</td><td> 505</td>

<td> 185</td><td>ΛΑ ΛΑ {A T CH, o = s = o A 0</td><td> 582,75</td><td> 59</td><td> 583</td>

522 809

MV

181

Exem-

<img file="SE522809C2_D0199.tif" />

522 809

182

Structure (g / mol) HPLC Mz + H

ExemMV pel nr

<td> 188</td><td colspan="2">CH. ⁰ ΓΗ »V 1 1 1 /,^NΖχ I CH, o = s = o z</td><td> 548,63</td><td> 73</td><td> 549</td>

<td></td><td colspan="2">9M »2 CH,</td><td></td><td></td><td></td>

<td></td><td>(j</td><td>ZaI&gt; '</td><td></td><td></td><td></td>

<td></td><td>IN!</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>I. ^CK3</td><td></td><td></td><td></td>

<td> 189</td><td> 0-</td><td>S z O</td><td> 548,63</td><td> 72</td><td> 549</td>

<td></td><td></td><td>xN</td><td></td><td></td><td></td>

<td></td><td>V Ν ' k</td><td>-N ?&gt; N</td><td></td><td></td><td></td>

522 809

183

MV

Exem-

<td colspan="2">pel nr Structure</td><td colspan="3">(g / mol) HPLC Mz + H</td>

<td> 190</td><td>0 Å-Γ 1 CH, o = s = o Cx X H, C ⁰</td><td> 559,67</td><td> 54</td><td> 560</td>

<td> 191</td><td>CH, 0 rw 1 CH, OH O = S = O V</td><td> 511,60</td><td> 70</td><td> 512</td>

522 809

MV

Example No. Structure (g / mol) HPLC Mz + H

<td> 192</td><td>CH, θ PH = io</td><td> 580,76</td><td> 68</td><td> 581</td>

<td> 193</td><td>CH, 0 -μ ϊ / D I CH, o = s = o N ^^ CH CH</td><td> 476,60</td><td> 89</td><td> 477</td>

<td> 194</td><td>&lt;; A I CH, o = s = o \ y °^hrs</td><td> 583,71</td><td> 80</td><td> 584</td>

522 809

185

ExemMV

<img file="SE522809C2_D0200.tif" />

522 809

186

<img file="SE522809C2_D0201.tif" />

Exem- MV

<img file="SE522809C2_D0202.tif" />

522 809

187

Exem- MV

<img file="SE522809C2_D0203.tif" />

522 809

Table 5:

188

Exem-

<img file="SE522809C2_D0204.tif" />

522 809

189

Exem-

<img file="SE522809C2_D0205.tif" />

Exem522 809

190

<img file="SE522809C2_D0206.tif" />

Exem522 809

191

<img file="SE522809C2_D0207.tif" />

522 809

192

Example No. Structure MV HPLC MZ + H

<td> 210</td><td>O_ N &lt;U</td><td>0 Α : Ο «,</td><td>Z-CH ί, CH</td><td> 560,72</td><td> 62</td><td> 561</td>

<td></td><td>Γ</td><td>1 Γ</td><td>-CH</td><td></td><td></td><td></td>

<td></td><td>Ό Ν '</td><td rowspan="2">Μν w</td><td></td><td></td><td></td><td></td>

<td></td><td>ιίΥ</td><td></td><td></td><td></td><td></td>

<td></td><td>Μ</td><td>V.</td><td>Λ</td><td></td><td></td><td></td>

<td> 211</td><td>τ o = s = o IN</td><td></td><td>CH</td><td> 568,7</td><td> 88</td><td> 569</td>

<td></td><td>1 Ν Ι</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Λ</td><td>CN,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">- * Ζ / ~ Όη</td><td></td><td></td><td></td>

<td></td><td>ϋ</td><td>å Γ</td><td>-CH</td><td></td><td></td><td></td>

<td></td><td>Ό Ν '</td><td rowspan="2">ν&gt;</td><td></td><td></td><td></td><td></td>

<td></td><td>ίΥ</td><td></td><td></td><td></td><td></td>

<td rowspan="2"> 212</td><td>V</td><td>V.</td><td rowspan="2">Λ CH</td><td> 582,73</td><td> 89</td><td> 583</td>

<td>o = s = o</td><td></td><td></td><td></td><td></td>

<td></td><td>Ν Ι</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Λ</td><td>CH</td><td></td><td></td><td></td><td></td>

<td></td><td>ΥΥ ^</td><td colspan="2"></td><td></td><td></td><td></td>

522 809

193

Example no

Structure

MV HPLC MZ + H

213

<img file="SE522809C2_D0208.tif" />

580,71

581

214 ζ XT

<img file="SE522809C2_D0209.tif" />

518,64

519

<img file="SE522809C2_D0210.tif" />

463,56

464

O = S = O

H, C

ΌΗ

215 x

522 809

194

Example No. Structure MV HPLC MZ + H

<td> 216</td><td>ϋ Å φΑ o = s = o 1 / A^m P Η, Α</td><td>R-CH CH</td><td> 548,71</td><td> 78</td><td> 549</td>

<td></td><td>CH, O l ll</td><td>R-CH</td><td></td><td></td><td></td>

<td></td><td>1 1 'ΛΑ</td><td> /^NX</td><td></td><td></td><td></td>

<td> 217</td><td>V</td><td>s</td><td> 490,63</td><td> 87</td><td> 491</td>

<td></td><td>T o = s = o |</td><td>CH</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 l 11</td><td>/ -CH</td><td></td><td></td><td></td>

<td></td><td>1 Λ</td><td>4 ί</td><td></td><td></td><td></td>

<td> 218</td><td>7 CH, O = S = O</td><td></td><td> 532,71</td><td> 93</td><td> 533</td>

<td></td><td>L N f</td><td></td><td></td><td></td><td></td>

<td></td><td>^ CH</td><td></td><td></td><td></td><td></td>

522 809

195

Exem-

<img file="SE522809C2_D0211.tif" />

522 809

196

Example no

Structure

MV HPLC MZ + H

<td> 221</td><td>ς, jpc 1 1 I / N Αλ 1 CH, o = s = o ^ • 'Sdh,</td><td> 516,67</td><td> 92</td><td> 517</td>

<td> 222</td><td>NV 1 1 I /,^N1 CH, CH, O = S = 0 hrs_inc^xN'^^/^^{/ Nx}-CH</td><td> 504,66</td><td> 83</td><td> 505</td>

<td> 223</td><td>ζ JyT I CH, ) -, O = s = 0 CH</td><td> 558,75</td><td> 90</td><td> 559</td>

522 809

197

Exem-

<img file="SE522809C2_D0212.tif" />

522 809

198

Exem-

<img file="SE522809C2_D0213.tif" />

522 809

199

Exem-

<img file="SE522809C2_D0214.tif" />

522 809

200

Exem-

<img file="SE522809C2_D0215.tif" />

522 809

201

Exem-

<img file="SE522809C2_D0216.tif" />

522 809

202

Exem-

<img file="SE522809C2_D0217.tif" />

522 809

203

Exem-

<img file="SE522809C2_D0218.tif" />

522 809 • ·

204

Table 6:

Example No. Structure MV HPLC MZ + H

<td> 243</td><td>k, 0 0-s = o in</td><td>0 V * -</td><td>, N X CH CH</td><td> 477,5869</td><td> 86</td><td> 478</td>

<td></td><td>ϋ</td><td>0 II</td><td>CH</td><td></td><td></td><td></td>

<td></td><td>^k0 Λ</td><td>HR '</td><td>A n ~ ^</td><td></td><td></td><td></td>

<td> 244</td><td>u</td><td></td><td></td><td> 495,605</td><td> 62</td><td> 496</td>

<td></td><td colspan="2">o = s = o 1</td><td>CH</td><td></td><td></td><td></td>

<td></td><td></td><td>V</td><td>Ί)</td><td></td><td></td><td></td>

<td></td><td></td><td>k</td><td></td><td></td><td></td><td></td>

<td></td><td>CH</td><td>0 II</td><td>CH</td><td></td><td></td><td></td>

<td></td><td>Ό h N</td><td>'T V^N</td><td>k_Nί</td><td></td><td></td><td></td>

<td> 245</td><td>V</td><td></td><td>s</td><td> 511,6044</td><td> 50</td><td> 512</td>

<td></td><td>T o = s = o</td><td></td><td>CH</td><td></td><td></td><td></td>

<td></td><td> | ^Nv</td><td>at</td><td></td><td></td><td></td><td></td>

<td></td><td>k</td><td>A&gt; -</td><td>_z^CH,</td><td></td><td></td><td></td>

522 809

205

Example No. Structure MV HPLC MZ + H

<img file="SE522809C2_D0219.tif" />

522 809

206

Example no

Structure

MV HPLC MZ + H

<td> 249</td><td>o K (X 0 = 1 = 0 σ, π CH</td><td>Λγ 1 λ^Νv ~ f</td><td> 581,6963</td><td> 77</td><td> 582</td>

<td></td><td>ϋ i</td><td>CH3</td><td></td><td></td><td></td>

<td></td><td></td><td rowspan="2">Λ A</td><td></td><td></td><td></td>

<td></td><td>xv</td><td></td><td></td><td></td>

<td></td><td>u</td><td></td><td></td><td></td><td></td>

<td> 250</td><td>T 0-s = o</td><td>CH</td><td> 557,6303</td><td> 76</td><td> 558</td>

<td></td><td> |</td><td></td><td></td><td></td><td></td>

<td></td><td> ^₀ΛΑ₀</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2"></td><td></td><td></td><td></td>

<td></td><td>ϋ 1</td><td></td><td></td><td></td><td></td>

<td></td><td>1 i Γ</td><td rowspan="2">A</td><td></td><td></td><td></td>

<td></td><td>/ * Uv</td><td></td><td></td><td></td>

<td> 251</td><td>Ψ o = s = o 1</td><td>CH</td><td> 539,615</td><td> 74</td><td> 540</td>

<td></td><td>Ύί</td><td></td><td></td><td></td><td></td>

<td></td><td>LY</td><td></td><td></td><td></td><td></td>

<td></td><td> 1 0</td><td>CH</td><td></td><td></td><td></td>

522 809

207

Example no

Structure MV HPLC MZ + H

<td> - 252</td><td>O 0^OAa o i_y^O- ^ - n^_zO</td><td>b .N X CH</td><td> 515,5677</td><td> 64</td><td> 516</td>

<td></td><td>CH, O L 11</td><td>CH3</td><td></td><td></td><td></td>

<td></td><td>i fr</td><td> &gt;</td><td></td><td></td><td></td>

<td></td><td>EAR-</td><td>b</td><td></td><td></td><td></td>

<td> 253</td><td>T</td><td rowspan="2">A CH</td><td> 472,5266</td><td> 38</td><td> 473</td>

<td></td><td>o = s = o |</td><td></td><td></td><td></td>

<td></td><td>N V,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ϋ i</td><td>cn</td><td></td><td></td><td></td>

<td></td><td></td><td rowspan="2">t</td><td></td><td></td><td></td>

<td></td><td>1 | T EAR-</td><td></td><td></td><td></td>

<td> 254</td><td>T</td><td rowspan="2">A</td><td> 459,5715</td><td> 88</td><td> 460</td>

<td></td><td>o = s = o IN</td><td></td><td></td><td></td>

<td></td><td>1 N b</td><td></td><td></td><td></td><td></td>

522 809

208

Exem-

<img file="SE522809C2_D0220.tif" />

522 809

209

Exem-

<img file="SE522809C2_D0221.tif" />

522 809

210

Example no

Structure MV HPLC MZ + H

<td> 261</td><td>o = s = o XX- CH, H, C</td><td>9 -CH</td><td>CH</td><td> 503,6687</td><td> 71</td><td> 504</td>

<td></td><td>CH l</td><td>0 II</td><td>CH</td><td></td><td></td><td></td>

<td></td><td> %</td><td>V</td><td>Λ Y</td><td></td><td></td><td></td>

<td> 262</td><td>7 o = s = o 1</td><td></td><td>s CH</td><td> 517,6086</td><td> 71</td><td> 518</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>II 0</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 l U</td><td colspan="2">CH</td><td></td><td></td><td></td>

<td></td><td>% X</td><td>.ΓΧΥ</td><td>N</td><td></td><td></td><td></td>

<td> 263</td><td>T ° F =</td><td>il</td><td>X CH</td><td> 511,6044</td><td> 76</td><td> 512</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">CH</td><td></td><td></td><td></td><td></td>

522 809

211

Ϋ

ExemMV HPLC MZ + H pel no

Structure

<td> 264</td><td>o = s = 1 N 00</td><td>xr ii /,^NOVX CH 0</td><td> 518,5989</td><td> 74</td><td> 519</td>

<td></td><td>ϋ</td><td>and V</td><td></td><td></td><td></td>

<td></td><td>Year</td><td>w</td><td></td><td></td><td></td>

<td> 265</td><td>O = &lt;X</td><td>'"IN</td><td> 552,6573</td><td> 91</td><td> 553</td>

<td></td><td></td><td>O</td><td></td><td></td><td></td>

<td></td><td>CH L</td><td>1 r</td><td></td><td></td><td></td>

<td></td><td>% Λ</td><td>O x</td><td></td><td></td><td></td>

<td> 266</td><td colspan="2">V \ T ^CH= o = s = o 1 n.</td><td> 566,6844</td><td> 71</td><td> 567</td>

<td></td><td>CH</td><td></td><td></td><td></td><td></td>

<td></td><td>u</td><td></td><td></td><td></td><td></td>

522 809

212

Example No. Structure MV HPLC MZ + H

<td> 267</td><td>o = s = o c</td><td>0 ύ X</td><td>.N CH</td><td> 567,6692</td><td> 48</td><td> 568</td>

<td></td><td>CN,</td><td> 0</td><td>CH3</td><td></td><td></td><td></td>

<td></td><td colspan="2"></td><td rowspan="2"> &gt;</td><td></td><td></td><td></td>

<td></td><td>IV</td><td>V '</td><td></td><td></td><td></td>

<td> 268</td><td>T o = s = o 1</td><td></td><td>s CH</td><td> 477,6084</td><td> 90</td><td> 478</td>

<td></td><td> 0</td><td></td><td></td><td></td><td></td><td> •</td>

<td></td><td>CH L</td><td>0 II</td><td></td><td></td><td></td><td></td>

<td></td><td>^k0</td><td>ir</td><td rowspan="2">t</td><td></td><td></td><td></td>

<td></td><td>Year</td><td></td><td></td><td></td><td></td>

<td> 269</td><td>T o = s = o</td><td></td><td>CH</td><td> 569,6851</td><td> 73</td><td> 570</td>

<td></td><td>| H, C^{/ Nx}-^/</td><td colspan="2"></td><td></td><td></td><td></td>

522 809

213

Exem-

<img file="SE522809C2_D0222.tif" />

pel nr

Structure MV HPLC MZ + H

<td> 270</td><td>dizzy T CHj ο ο = ψ = OH</td><td> 651,766</td><td> 65</td><td> 652</td>

<td> 271</td><td>χ χτ (Υ^νΆ T CH, o = s = o 1 A Αγ \_ΗT / 0 al</td><td> 541,6309</td><td> 71</td><td> 542</td>

<td> 272</td><td>άΧ T CH, o = s = o dizzy¹</td><td> 607,6133</td><td> 39</td><td> 608</td>

522 809

214

<img file="SE522809C2_D0223.tif" />

ExemMV HPLC MZ + H pel no

Structure

<td> 273</td><td>Ear o = f = ° OH /</td><td> 511,6044</td><td> 92</td><td> 512</td>

<td> 274</td><td>Λζ Λζ 1 1 ι A (pR HO JGJ</td><td> 589,7164</td><td> &gt;95</td><td> 590</td>

<td> 275</td><td>c .pr T CH, o = s = o in hrs₃c^/^^{x / N}'^^xOH</td><td> 477,5869</td><td> &gt;95</td><td> 478</td>

522 809

215

ExemStructure MV HPLC MZ + H

<td> 276</td><td>ζ J /³I CH, o = s = o Η, Ο ^ ^ Ν θΠ</td><td> 463,5598</td><td> 64</td><td> 464</td>

<td> 277</td><td>ζ, Λ /⁴1 CH, o == s = o 1</td><td> 449,5327</td><td> &gt;95</td><td> 450</td>

<td> 278</td><td>^{o =}v&gt;&gt; O z £</td><td> 507,6134</td><td> &gt;95</td><td> 508</td>

522 809

216

Exem-

<td>pel nr</td><td>Structure</td><td>MV</td><td colspan="2">HPLC MZ + H</td>

<td></td><td>ζ A / ·</td><td></td><td></td><td></td>

<td></td><td>US</td><td></td><td></td><td></td>

<td> 279</td><td> 1 ^CH3 o = s = o \</td><td> 532,6232</td><td> &gt;95</td><td> 533</td>

<td></td><td>O %</td><td></td><td></td><td></td>

<td></td><td>1 CH</td><td></td><td></td><td></td>

<td></td><td>k A / (Vn</td><td></td><td></td><td></td>

<td> 280</td><td>US T CH, 0-S-O 1</td><td> 560,6775</td><td> 89</td><td> 561</td>

<td></td><td>O_Yo_.cn, M4H,</td><td></td><td></td><td></td>

522 809

217

Exem-

<td>pel nr</td><td colspan="2">Structure</td><td>MV</td><td>HPLC</td><td>MZ + H</td>

<td></td><td>CH. f</td><td> ¢4</td><td></td><td></td><td></td>

<td> 281</td><td>l o =:</td><td> 5=0</td><td> 636,8199</td><td> 88</td><td> 637</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>0 Λ</td><td>Az ii //^NM</td><td></td><td></td><td></td>

<td> 282</td><td>T o = s = c 1</td><td></td><td> 476,5585</td><td> 50</td><td> 477</td>

<td></td><td>σ '</td><td></td><td></td><td></td><td></td>

<td></td><td>CH. 1</td><td>ft /^CH</td><td></td><td></td><td></td>

<td></td><td colspan="2">ό f / yA ΑΛΡ "</td><td></td><td></td><td></td>

<td> 283</td><td>o = s = o island</td><td>CH</td><td> 489,5981</td><td> 93</td><td> 490</td>

<td></td><td>J</td><td></td><td></td><td></td><td></td>

*

522 809

218

Example No. Structure MV HPLC MZ + H

<td> 284</td><td>Of T CH, 0 — S — 0</td><td> 622,7928</td><td> 68</td><td> 623</td>

<td> 285</td><td>Λ Λ /¹A; 1 CH, o = s = o CP -D</td><td> 608,7657</td><td> &gt;95</td><td> 609</td>

<td> 286</td><td>ζ Å / όΆ T CH, o = s = o skin OH</td><td> 583,6873</td><td> 85</td><td> 584</td>

522 809

Exem219

<img file="SE522809C2_D0224.tif" />

Exem522 809

220 pel nr

Structure

MV HPLC MZ + H

<td> 290</td><td>o · \ T CH, », T ^ 0</td><td> 571,6574</td><td> 73</td><td> 572</td>

<td> 291</td><td>(YES o = s = o 1 N Å * H &lt;°</td><td> 569,6851</td><td> 83</td><td> 570</td>

<td> 292</td><td>ζ Oh XOT, T CH, o = s = o in</td><td> 597,7393</td><td> 89</td><td> 598</td>

522 809

221

Example no

Structure

MV HPLC MZ + H

293

<img file="SE522809C2_D0225.tif" />

CH

<img file="SE522809C2_D0226.tif" />

581,6963

609,7504

582

610

294

522 809

222

Example no

Structure

MV HPLC MZ + H

<img file="SE522809C2_D0227.tif" />

522 809

223

Example no

Structure

MV HPLC MZ + H

<td> 298</td><td>A * ·; C &lt; CH</td><td> 571,6574</td><td> 89</td><td> 572</td>

<td> 299</td><td>Λ Λ / I CH, 0-s = o CH</td><td> 567,6692</td><td> 81</td><td> 568</td>

<td> 300</td><td>o = s = o N c, °</td><td> 627,7221</td><td> 82</td><td> 628</td>

522 809

224

Example no

Structure

MV HPLC MZ + H

<td> 301</td><td>o = s = o XA '' CH</td><td> 661,7396</td><td> 64</td><td> 662</td>

<td> 302</td><td>ζ -V o = s = o aZ k</td><td> 599,668</td><td> 77</td><td> 600</td>

<td> 303</td><td>and M Zx 1 CH, o = s = o IN CH, CH,</td><td> 555,658</td><td> 83</td><td> 556</td>

522 809

Example No. Structure MV HPLC MZ + H

<td> 304</td><td>AA T CH, o = s = o J -</td><td> 654,7916</td><td> 60</td><td> 655</td>

<td> 305</td><td>TOE? T_ 5li O x CH</td><td> 626,7374</td><td> 86</td><td> 627</td>

<td> 306</td><td>3 &lt; O 1 O &lt;&gt; A sr</td><td> 627,7221</td><td> 82</td><td> 628</td>

522 809

226

Example no

Structure

MV HPLC MZ + H

<td> 307</td><td></td><td colspan="2">ζ. * X O = S = O / N IN</td><td> 583,7122</td><td> 81</td><td> 584</td>

<td></td><td></td><td colspan="2">J? ° '° Λ</td><td></td><td></td><td></td>

<td> 308</td><td></td><td>ζ, 9 o = s = o 1 N 1</td><td>v ii /,^NSXF G</td><td> 631,7568</td><td> 29</td><td> 632</td>

<td></td><td>O</td><td>A</td><td></td><td></td><td></td><td></td>

<td> 309</td><td></td><td colspan="2">ς, .yr o = s = o 1</td><td> 569,6851</td><td> 60</td><td> 570</td>

<td></td><td>CH</td><td></td><td></td><td></td><td></td><td></td>

522 809

227

Example No. Structure MV HPLC MZ + H

<td> 310</td><td>II 1, n T CH, O-S-0 H, &lt;T ° CH,</td><td> 597,7393</td><td> 62</td><td> 598</td>

<td> 311</td><td>O jAS £</td><td> 581,6963</td><td> 87</td><td> 582</td>

<td> 312</td><td>r 1? 44 0_s = o CT'A</td><td> 609,7504</td><td> 71</td><td> 610</td>

522 809

228

Example no

Structure MV HPLC MZ + H

<td> 313</td><td>0 - = 0 cyAk &lt;SAJ</td><td> 633,7291</td><td> 47</td><td> 634</td>

<td> 314</td><td>f Å F .yk, o = s = o £ f ; rX</td><td> 570,629</td><td> 59</td><td> 571</td>

<td> 315</td><td>o = s = o</td><td> 633,7291</td><td> 35</td><td> 634</td>

522 809

229

Example no

Structure MV HPLC MZ + H

<td> 316</td><td>X 1 CH, T : Xr " Η, σ ^ ΟΗ,</td><td> 583,7122</td><td> 51</td><td> 584</td>

<td> 317</td><td>1 1, N XX T CH, 0 = S = O O, V</td><td> 611,7227</td><td> 51</td><td> 612</td>

<td> 318</td><td>ι ι I -, n X T CH, 0-s = o O_xCH</td><td> 571,6574</td><td> 75</td><td> 572</td>

522 809

230 • *

MV HPLC MZ + H

Example no

Structure

<td> 319</td><td>SA A o = s = o A ό</td><td> 603,7026</td><td> 64</td><td> 604</td>

<td> 320</td><td>k ÅT T CHj o = s = o fa 0 ^ A</td><td> 567,6692</td><td> 74</td><td> 568</td>

<td> 321</td><td>w Ear 1 CH, o = s = o A kA</td><td> 597,652</td><td> 88</td><td> 598</td>

522 809

231

Sxem] »el nr Structure MV HPLC MZ + H

<td> 322</td><td>aa 0 = 4 = 0 ^CH&gt; 0H, S</td><td> 627,7221</td><td> 80</td><td> 628</td>

<td> 323</td><td>OF c + Ά I CH, o = | = o XT cn ^ X</td><td> 647,7562</td><td> 47</td><td> 648</td>

<td> 324</td><td>A Ap X Q - S — O CH * A CH, ^ CH,</td><td> 555,658</td><td> 43</td><td> 556</td>

Example No. Structure MV HPLC MZ + H

522 809

232

<td> 325</td><td>ζ, A o = s = o »/ -A y </td><td> 654,7916</td><td> 54</td><td> 655</td>

<td> 326</td><td>ϊζ A in &lt;yA</td><td> 624,7214</td><td> 71</td><td> 625</td>

<td> 327</td><td>w:₀ T_?A hrs</td><td> 689,8375</td><td> 42</td><td> 690</td>

522 809

233

Example no

Structure MV HPLC MZ + H

<td> 328</td><td>T CH, o-S = O CH</td><td> 583,7122</td><td> 40</td><td> 584</td>

<td> 329</td><td>O X) Q. 2</td><td> 555,658</td><td> 49</td><td> 556</td>

<td> 330</td><td>CH, 0 pu ^chiralL AX 1 CH, o = s = o -Y</td><td> 525,6315</td><td> 83</td><td> 526</td>

<img file="SE522809C2_D0228.tif" />

Exem522 809

234

<img file="SE522809C2_D0229.tif" />

522 809

235 pel nr Structure MV HPLC MZ + H

Exem-

<td> 334</td><td>^ 0 NV Χν-ζ I CH, o = s = o 1</td><td> 478,5745</td><td> 62</td><td> 479</td>

<td> 335</td><td>ζ, v (Y^v\ T CH, 0 = 5 = 0 N X</td><td> 490,6292</td><td> 42</td><td> 491</td>

522 809 PRU00 05: L

236

Example 336

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

<img file="SE522809C2_D0230.tif" />

Crystallizing the free base from Example 19 from a mixture of an organic solvent and dilute aqueous hydrochloric acid gives a hydrochloride trihydrate.

Mp: 218 ° C

Water content: 9.4% (K. Fischer)

Chloride content: 6.1%

522 809

237

Example 337

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

<img file="SE522809C2_D0231.tif" />

0.35 g (0.712 mmol) 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1] [1,2] , 4] triazin-4-one is suspended in 8 ml of ether and dichloromethane is added in such an amount that a homogeneous solution is formed. 2.4 ml of a 1M solution of HCl in ether are added, stirred for 20 minutes at room temperature and the substance is filtered off with suction. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1] [1] are obtained. , 2,4] triazine-4-one dihydrochloride.

200 MHz 1 H-NMR (DMSO-d 6): 0.96, ζ 3H; 1.22, 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, 4H; 4.25, quart., 2H;

7.48, d, 1 H; 7.95, m. 2H; 11.42, s, 1 H; 12.45, s, 1H.

522 809

238