# Patent

## Title
7-Alkyl and cycloalkyl-substituted imidazotriazinones

## Abstract

The present invention relates to 7-alkyl- and cycloalkyl-substituted imidazotriazinones, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.

## Background
This application is a continuing application of U.S. Ser. No. 10/251,939, filed Sep. 20, 2002, now U.S. Pat. No. 6,838,459 which is a continuation of U.S. Ser. No. 09/720,051, filed Mar, 23, 2001, now U.S. Pat. No. 6,476,029.


The present invention relates to 7-alkyl- and cycloalkyl-substituted imidazotriazinones, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The published specification DE-28 11 780 describes imidazotriazines as bronchodilators having spasmolytic activity and inhibitory activity against phosphodiesterases which metabolize cyclic adenosine monophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III and PDE-IV). An inhibitory action against phosphodiesterases which metabolize cyclic guanosine monophosphate (cGMP-PDEs, nomenclature according to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) has not been described. Compounds having a sulphonamide group in the aryl radical in the 2 position are not claimed. Furthermore, FR 22 13 058, CH-59 46 71, DE-22 55 172, DE-23 64 076 and EP-000 9384 describe imidazotriazinones which do not have a substituted aryl radical in the 2 position and are likewise said to be bronchodilators having cAMP-PDE-inhibitory action.
The compounds according to the invention are potent inhibitors either of one or of more of the phosphodiesterases which metabolize cyclic guanosine 3′,5′-monophosphate (cGMP-PDEs). 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 can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic, vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of muscular and cardiac inotropy, of the pulse and of cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas and C. Lugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
The present invention, accordingly, provides 7-alkyl- and cycloalkyl-substituted imidazotriazinones of the general formula (I) 




in which

    R1 represents straight-chain or branched alkyl having up to 4 carbon atoms,
    R2 represent straight-chain [lacuna] having at least 5 carbon atoms or branched alkyl having at least 3 carbon atoms, or represents cycloalkyl having 3 to 10 carbon atoms,
    R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 8 carbon atoms, or represent 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 mono- to trisubstituted by identical or different substituents from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 6 carbon atoms and/or by radicals of the formulae —SO3H, -(A)a-NR7R8, —O—CO—NR7′R8′, —S(O)b—R9, HN═SO—R9′, —P(O)(OR10)(OR11), 




     in which
    
        a and b are identical or different and represent a number 0 or 1,
        A represents a radical CO or SO2,
        R7, R7′, R8 and R8′ are identical or different and represent hydrogen, or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(SO2)c—NR12R13,
        
            in which
            c represents a number 0 or 1,
            R12 and R13 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or
        
        
        R7, R7′, R8 and R8′ represent straight-chain or branched alkoxy having up to 6 carbon atoms, or represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, aryl having from 6 to 10 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(CO)d—NR14R15,
        
            in which
            R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and
            d represents a number 0 or 1, or
        
        
        R7 and R8 and/or R7′ and R8′ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR16,
        
            in which
            R16 represents hydrogen, aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl,
        
        
        R9 and R9′ are identical or different and represent aryl having 6 to 10 carbon atoms or benzyl, or represent straight-chain or branched alkyl having up to 4 carbon atoms,
        R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
        and/or the alkyl chain listed above under R3/R4 is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 ring heteroatoms from the group consisting of S, N, O or a radical of the formula —NR7, where the alkyl chain may optionally also be attached via a ring nitrogen atom,
        
            in which
            R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms,
        
        
    
    
    and where aryl and the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of nitro, halogen, —SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO2)e—R18R19,
    
        in which
        e represents a number 0 or 1,
        R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 6 carbon atoms, and/or
    
    
    R3 or R4 represent radicals of the formulae —NR20R21 or —(O)-E-NR22R23,
    
        in which
        R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a 5- or 6-membered saturated heterocycle having a further ring heterocycle from the group consisting of S and O or a radical —NR24,
        
            in which
            R24 has the meaning of R16 given above and is identical to or different from this meaning,
        
        
        E is a straight-chain alkylene group having up to 5 carbon atoms,
        R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning, and/or
    
    
    R3 or R4 represent radicals of the formulae 




     or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered partially unsaturated, saturated and unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N, O or a radical of the formula —NR25 which may optionally also be attached via a ring nitrogen atom,
    
         in which
        R25 has the meaning of R16 given above and is identical to or different from this meaning, or represents carboxyl, formyl or straight-chain or branched acyl having up to 5 carbon atoms, and where cycloalkyl, aryl and/or the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and/or by groups of the formulae —SO3H, —OR26, (SO2)fNR27R28, —P(O)(OR29)(OR30),
        
            in which
            R26 represents a radical of the formula 




             or represents cycloalkyl having 3 to 7 carbon atoms, or hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen,
            
                f is a number 0 or 1,
                R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula —CO—NH2,
                R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
            
            
        
        
    
    
    and/or cycloalkyl, aryl and/or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or by groups of the formulae —SO2—R31, P(O)(OR32)(OR33) or —NR34R35,
    
        in which
        R31 is hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
        R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or
        R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR36,
        
            in which
            R36 has the meaning of R16 given above and is identical to or different from this meaning, or
        
        
    
    
    R3 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N, O or a radical of the formula —NR37,
    
        in which
        R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms, or
        R37 represents a radical of the formula —(CO)g-G,
        
            in which
            g represents a number 0 or 1,
            G represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 6 carbon atoms, hydroxyl and trifluoromethyl,
        
        
    
    
    and the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 6 carbon atoms and groups of the formulae —P(O)(OR38)(OR39) and —(CO)g)—NR40R41,
    
        in which
        R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        g represents a number 0 or 1, and
        R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
    
    
    and/or the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a radical of the formula —SO3H, —NR42R43 or P(O)OR44OR45,
    
        in which
        R42 and R43 are identical 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,
        R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
    
    
    and/or the alkyl is optionally substituted by benzyloxy or aryl having 6 to 10 carbon atoms, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy or alkylthio having in each case up to 6 carbon atoms, or by a group of the formula —NR42′R43′,
    
        in which
        R42′ and R43′ have the meaning of R42 and R43 given above and are identical to or different from this meaning,
    
    
    and/or the heterocycle mentioned under R3 and R4, formed via a nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 ring heteroatoms from the group consisting of S, N and/or O, optionally also attached via an N function, where the ring systems for their part may be substituted by halogen, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, or
    R3 and R4 together with the nitrogen atom form radicals of the formulae 




     in which
    
        R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 6 carbon atoms,
        R45 and R45′ are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
        R46 represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,
    
    
    R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxy or represents straight-chain or branched alkoxy having up to 6 carbon atoms,
    and their salts and isomeric forms.


The compounds according to the invention may exist in stereoisomeric forms which are either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms can, just like the diastereomers, be separated in a known manner into the stereoisomerically uniform constituents.
The substances according to the invention may also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
In the context of the invention and depending on the various substituents, optionally benzo-fused heterocycle generally represents an aromatic, saturated, partially unsaturated or unsaturated 5- to 7-membered or 5- to 6-membered heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are: azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, imidazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl or piperidinyl. Preference is given to quinolyl, furyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, piperazinyl, azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, tetrahydropyranyl, morphholinyl and thiomorpholinyl.
Preference is given to compounds of the general formula (I) according to the invention
in which


    R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
    R2 represents straight-chain [lacuna] having 5 to 15 carbon atoms or branched alkyl having 3 to 15 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
    R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 4 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 4 carbon atoms and/or by radicals of the formulae —SO3H, -(A)a—NR7R8, —O—CO—NR7′R8′, —S(O)b—R9, HN═SO—R9′, —P(O)(OR10)(OR11), 



    
        in which
        a and b are identical or different and represent a number 0 or 1,
        A represents a radical CO or SO2,
        R7, R7′, R8 and R8′ are identical or different and represent hydrogen, or represent phenyl, naphthyl, or pyridyl, where the ring systems listed above are optionally mono- to disubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or represent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, bromine, phenyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a group of the formula —(CO)d—NR14R15,
        
            in which
            R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and
            d represents a number 0 or 1, or
        
        
        R7 and R8 and/or R7′ and R8′ together with the nitrogen atom form a pyrrolidinyl, piperidinyl or morpholinyl ring or a radical of the formula 




         in which
        
            R16 represents hydrogen, phenyl, naphthyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl,
        
        
        R9 and R9′ are identical or different and represent phenyl or benzyl, or represent straight-chain or branched alkyl having up to 3 carbon atoms,
        R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
        and/or the alkyl chain mentioned above under R3/R4 is optionally substituted by phenyl, naphthyl, morpholinyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl or thienyl, where the radical may optionally also be attached to the alkyl chain via a ring nitrogen atom,
    
    
    and where aryl and the heterocycle are optionally mono- to disubstituted by identical or different substituents from the group consisting of nitro, fluorine, chlorine, bromine, —SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO2)e—NR18R19,
    
        in which
        e represents a number 0 or 1,
        R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms, and/or
    
    
    R3 and R4 represent radicals of the formulae —NR20R21 or —(O)-E-NR22R23,
    
        in which
        R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a morpholinyl ring, pyrrolidinyl ring or a radical of the formula 



        
            in which
            R24 has the meaning of R16 given above and is identical to or different from this meaning,
        
        
        E represents a straight-chain alkylene group having up to 4 carbon atoms,
        R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning, and/or
    
    
    R3 or R4 represent radicals of the formulae 




     or represent cyclopentyl, cyclohexyl, naphthyl, phenyl, pyridyl, or quinolyl or tetrazolyl attached via the phenyl ring, and where the ring systems given above are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 4 carbon atoms and/or by groups of the formulae —SO3H, —OR26, (SO2)fNR27R28, —P(O)(OR29)(OR30),
    
        in which
        R26 represents a radical of the formula 




         or represents cyclopentyl or cyclohexyl, or represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to disubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl and halogen,
        f represents a number 0 or 1,
        R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula —CO—NH2,
        R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
    
    
    and/or the ring systems given above are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which are optionally substituted by hydroxyl, carboxyl, morpholine, pyridyl or by groups of the formula —SO2—R31, P(O)(OR32)(OR33) or —NR34R31,
    
        in which
        R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
        R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
        R34 and R35 together with the nitrogen atom form a morpholinyl, pyrrolidinyl, piperidinyl ring or a radical of the formula 




         in which
        
            R36 has the meaning of R16 given above and is identical to or different from this meaning, or
        
        
    
    
    R3 and R4 together with the nitrogen atom form a piperidinyl, pyrrolidinyl or morpholinyl ring, or a radical of the formula 




     in which
    
        R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or
        R37 represents a radical of the formula —(CO)g-G,
        
            in which
            g represents a number 0 or 1,
            G represents naphthyl, phenyl, pyridyl or pyrimidyl, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 4 carbon atoms, hydroxyl and trifluoromethyl,
        
        
    
    
    and the heterocycles listed above under R3 and R4 are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms and groups of the formulae —P(O)(OR38)(OR39) or —(CO)g)—NR40R41,
    
        in which
        R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        g represents a number 0 or 1, and
        R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
    
    
    and/or the heterocycles listed under R3 and R4 are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a radical of the formula —SO3H, —NR42R43 or P(O)OR44OR45,
    
        in which
        R42 and R43 are identical or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
        R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
    
    
    and/or the alkyl is optionally substituted by benzyloxy, naphtyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy and alkylthio having in each case up to 4 carbon atoms, or by a group of the formula —NR42R43,
    
        in which
        R42′ and R43′ have the meaning of R42 and R43 given above and are identical to or different from this meaning,
    
    
    and/or the heterocycles listed under R3 and R4 are optionally substituted by phenyl, naphthyl or by radicals of the formulae 




     where the ring systems for their part may be substituted by fluorine, chlorine, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, or
    R3 and R4 together with the nitrogen atom form radicals of the formulae 




     in which
    
        R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
        R45 and R45′ are identical or different and represent hydrogen or methyl,
        R46 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
    
    
    R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, hydroxyl or represent straight-chain or branched alkoxy having up to 4 carbon atoms,

and their salts and isomeric forms.



Particular preference is given to compounds of the general formula (I) according to the invention,
in which


    R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
    R2 represents straight-chain [lacuna] having 5 to 12 carbon atoms or branched alkyl having 3 to 12 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
    R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 4 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 4 carbon atoms and/or by radicals of the formulae —SO3H, -(A)a-NR7R8, —O—CO—NR7′R8′, —S(O)b—R9, HN═SO—R9′, —P(O)(OR10)(OR11), 




     in which
    
        a and b are identical or different and represent a number 0 or 1,
        A represents a radical CO or SO2,
        R7, R7′, R8 and R8′ are identical or different and represent hydrogen, or represent phenyl, naphthyl, or pyridyl, where the ring systems listed above are optionally mono- to disubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or represent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, bromine, phenyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a group of the formula —(CO)d—NR14R15,
        
            in which
            R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and
            d represents a number 0 or 1, or
        
        
        R7 and R8 and/or R7′ and R8′ together with the nitrogen atom form a pyrrolidinyl, piperidinyl or morpholinyl ring or a radical of the formula 




         in which
        
            R16 represents hydrogen, phenyl, naphthyl or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl,
        
        
        R9 and R9′ are identical or different and represent phenyl or benzyl, or represent straight-chain or branched alkyl having up to 3 carbon atoms,
        R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
        and/or the alkyl chain listed above under R3/R4 is optionally substituted by phenyl, naphthyl, morpholinyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl or thienyl, where the attachment to the alkyl chain may optionally also take place via a ring nitrogen atom,
    
    
    and where aryl and the heterocycle are optionally mono- to disubstituted by identical or different substituents from the group consisting of nitro, fluorine, chlorine, bromine, —SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO2)e—NR18R19,
    
        in which
        e represents a number 0 or 1,
        R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms, and/or
    
    
    R3 or R4 represents radicals of the formulae —NR20R21 or —(O)-E-NR22R23,
    
        in which
        R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a morpholinyl ring, pyrrolidinyl ring or a radical of the formula 




         in which
        
            R24 has the meaning of R16 given above and is identical to or different from this meaning,
        
        
        E represents a straight-chain alkylene group having up to 4 carbon atoms,
        R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning and/or
    
    
    R3 or R4 represent the radicals of the formulae 




     or represent cyclopentyl, cyclohexyl, naphthyl, phenyl, pyridyl, or quinolinyl or tetrazolyl attached via the phenyl ring, and where the ring systems given above are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 4 carbon atoms and/or by groups of the formulae —SO3H, —OR26, (SO2)fNR27R28, —P(O)(OR29)(OR30),
    
        in which
        R26 represents a radical of the formula 




         or represents cyclopentyl or cyclohexyl, or represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to disubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl and halogen,
        f represents a number 0 or 1,
        R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula —CO—NH2,
        R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
    
    
    and/or the ring systems given above are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which are optionally substituted by hydroxyl, carboxyl, morpholine, pyridyl or by groups of the formula —SO2—R31, P(O)(OR32)(OR33) or —NR34R35,
    
        in which
        R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
        R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
        R34 and R35 together with the nitrogen atom form a morpholinyl, pyrrolidinyl, piperidinyl ring or a radical of the formula 




         in which
        
            R36 has the meaning of R16 given above and is identical to or different from this meaning, or
        
        
    
    
    R3 and R4 together with the nitrogen atom form a piperidinyl, pyrrolidinyl or morpholinyl ring, or a radical of the formula 




     in which
    
        R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or
        R37 represents a radical of the formula —(CO)g-G,
        
            in which
            g represents a number 0 or 1,
            G represents naphthyl, phenyl, pyridyl or pyrimidyl, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 4 carbon atoms, hydroxyl and trifluoromethyl,
        
        
    
    
    and the heterocycles listed under R3 and R4 are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms and groups of the formulae —P(O)(OR38)(OR39) or —(CO)g)—NR40R41,
    
        in which
        R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
        g represents a number 0 or 1, and
        R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
    
    
    and/or the heterocycles listed under R3 and R4 are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a radical of the formula —SO3H, —NR42R43 or P(O)OR44OR45,
    
        in which
        R42 and R43 are identical or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
        R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
        and/or the alkyl is optionally substituted by benzyloxy, naphtyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy or alkylthio having in each case up to 4 carbon atoms, or by a group of the formula NR42′R43′
        in which
        R42′ and R43′ have the meaning of R42 and R43 given above and are identical to or different from this meaning,
    
    
    and/or the heterocycles listed under R3 and R4 are optionally substituted by phenyl, naphthyl or by radicals of the formulae 




     where the ring systems for their part may be substituted by fluorine, chlorine, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, or
    R3 and R4 together with the nitrogen atom form radicals of the formulae 




     in which
    
        R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
        R45 and R45′ are identical or different and represent hydrogen or methyl,
        R46 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
    
    
    R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, hydroxyl or represent straight-chain or branched alkoxy having up to 4 carbon atoms,

and their salts and isomeric forms.



Particular preference is also given to compounds of the general formula (I) in which

    R1 represents methyl or ethyl,
    R2 represents straight-chain [lacuna] having 5 to 11 carbon atoms or branched alkyl having 3 to 11 carbon atoms, or represents cyclopentyl, cyclohexyl, cycloheptyl,
    R3 and R4 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, morpholinyl, methoxy, ethoxy, N,N-dimethylamino, N,N-diethylamine or phenyl, which for its part may be substituted up to 3 times by identical or different substituents from the group consisting of methoxy, or represents cyclopropyl, or or represents phenyl which is optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine or hydroxyl, methoxy, ethoxy, fluorine or by straight-chain or branched alkyl having up to 3 carbon atoms, which for its part may be substituted by hydroxyl, or
    R3 and R4 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring which are optionally substituted by hydroxyl or by radicals of the formulae —P(O)(OC2H5)2 or —CH2—P(O)OH(OC2H5) or by straight-chain or branched alkyl having up to 3 carbon atoms, which for its part may be substituted by hydroxyl or methoxy, or or
    R3 and R4 together with the nitrogen atom form a radical of the formula 




     in which
    
        R37 represents pyrimidyl, ethoxycarbonyl or a radical of the formula —CH2—P(O)(OCH3)2 or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl or methoxy,
    
    
    R5 represents hydrogen, and
    R6 represents ethoxy,

and their salts and isomeric forms.



Particular preference is furthermore given to compounds of the general formula (I) according to the invention in which R5 represents hydrogen and the ethoxy group is in the O position to the point of attachment of the heterocycle.
Very particular preference is given to compounds according to the invention having the following structures:










Structure






























































































































Moreover, we have found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that
[A] initially compounds of the general formula (II) 




in which

    R1 and R2 are as defined above and
    L represents straight-chain or branched alkyl having up to 4 carbon atoms,
    are converted with compounds of the general formula (III) 




in which

    R5 and R6 are as defined above
    in a two-step reaction, preferably using the system ethanol and then phosphorus oxytrichloride/dichloroethane, into the compounds of the general formula (IV) 




in which

    R1, R2, R5 and R6 are as defined above,
    in a further step reacted with chlorosulphonic acid to give the compounds of the general formula (V) 




     in which
    R1, R2, R1 and R6 are as defined above,
    and then reacted with amines of the general formula (VI)

HN3R4  (VI)

in which

    R3 and R4 are as defined above
    in inert solvents.


The process according to the invention can be illustrated in an exemplary manner by the equations below: 




Solvents which are suitable for the individual steps are the customary 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 mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the above-mentioned solvents. Particular preference is given to ethanol for the first step and dichloroethane for the second step.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from −20° C. to 200° C., preferably of from 0° C. to 70° C.
The process steps according to the invention are generally carried out under atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).
The reaction to give the compounds of the general formula (V) is carried out in a temperature range of from 0° C. to room temperature, and at atmospheric pressure.
The reaction with the amines of the general formula (VI) is carried out in one of the abovementioned chlorinated hydrocarbons, preferably in dichloromethane.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out at temperatures in a range of from −20° C. to 200° C., preferably of from 0° C. to room temperature.
The reaction is generally carried out at atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example in a range of from 0.5 to 5 bar).
Some of the compounds of the general formula (II) are known, or they are novel, and they can then be prepared by

    converting compounds of the general formula (VII)

R2—CO-T  (VII)

in which

    R2 is as defined above and
    T represents halogen, preferably represents chlorine,
    initially by reaction with compounds of the general formula (VIII) 




in which

    R1 is as defined above
    in inert solvents, if appropriate in the presence of a base and trimethylsilyl chloride, into the compounds of the general formula (IX) 




in which

    R1 and R2 are each as defined above,
    and finally reacting with the compound of the formula (X) 




in inert solvents, if appropriate in the presence of a base.



Suitable solvents for the individual steps of the process are the customary 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 mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the above-mentioned solvents. Particular preference is given to dichloromethane for the first step and to a mixture of tetrahydrofuran and pyridine for the second step.
Suitable bases are generally alkali metal hydrides or alkali metal alkoxides, such as, for example, sodium hydride or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C1-C4 alkylamines, such as, for example, triethylamine. Preference is given to triethylamine, pyridine and/or dimethylaminopyridine.
The base is generally employed in an amount of from 1 mol to 4 mol, preferably from 1.2 mol to 3 mol, in each case based on 1 mol of the compound of the formula (X).
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from −20° C. to 200° C., preferably of from 0° C. to 100° C.
The compounds of the general formulae (VII), (VIII), (IX) and (X) are known per se, or they can be prepared by customary methods.
The compounds of the general formula (II) can be prepared by

    reacting compounds of the general formula (XI) 




in which

    R5 and R6 are each as defined above
    with ammonium chloride in toluene and in the presence of trimethylaluminium in hexane in a temperature range of from −20° C. to room temperature, preferably at 0° C. and atmospheric pressure, and reacting the resulting amidine, if appropriate in situ, with hydrazine hydrate, to give the compounds of the general formula (III).


The compounds of the general formula (XI) are known per se, or they can be prepared by customary methods.
Most of the compounds of the general formula (IV) and (V) are novel, and they can be prepared as described above.
The amines of the general formula (VI) are known or can be prepared by customary methods.
The compounds of the general formula (I) according to the invention have an unforeseeable useful pharmacological activity spectrum.
They inhibit either one or more of the cGMP-metabolizing phosphodiesterases (PDE I, PDE II and PDE V). This results in an increase of cGMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with the selective inhibitors according to the invention make it possible to selectively address the various cGMP-regulated processes.
Moreover, the compounds according to the invention enhance the activity of substances such as, for example EDRF (endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances which increase the cGMP concentration in a manner different from that of phosphodiesterase inhibitors.
They can therefore be employed in pharmaceuticals for treating cardiovascular disorders, such as, for example, for treating hypertension, neuronal hypertonia, stable and unstable angina, peripheral and cardial vasculopathies, arrhythmiae, for treating thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transistory and ischaemic attacks, angina pectoris, obstruction of peripheral circulation, prevention of restenoses after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass. Furthermore, they may also be of significance for cerebrovascular disorders.
They are also suitable for treating all disorders in which a relaxing action on smooth muscles is of importance, such as, for example, erectile dysfunction and female sexual dysfunction.
Activity of the Phosphodiesterases (PDEs)
The cGMP-stimulated PDE II, the cGMP-inhibited PDE III and the cAMP-specific PDE IV were isolated either from porcine or bovine heart myocardium. The Ca2+-calmodulin-stimulated PDE I was isolated from porcine aorta, porcine brain or, preferably, from bovine aorta. The cGMP-specific PDE V was obtained from porcine small intestine, porcine aorta, human platelets and, preferably, from bovine aorta.
Purification was carried out by anion exchange chromatography over MonoQ® Pharmacia, essentially following the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al., Biochemical Pharmacology, Vol. 35, 1743-1751 (1986).
The “phosphodiesterase [3H] cAMP-SPA enzyme assay” and the “phosphodiesterase [3H] cGMP-SPA enzyme assay” from Amersham Life Science were used for determining enzyme activity and IC50 values of the various substances. The test was carried out according to the test protocol of the manufacturer. To determine the activity of PDE2, the [3H]cAMP SPA assay was used, and 10−6 M cGMP were added to the reaction mixture to activate the enzyme. To measure PDE1, 10−7 M calmodulin and 1 mM CaCl2 were added to the reaction mixture. PDE5 was measured using the [3H]cGMP SPA assay.
The substances preferably inhibit phosphodiesterases I and V. For both enzymes, the IC50 values are in the range from 500 [lacuna] to 1 mM for PDE V preferably in the range from 1 to 100, for PDE I preferably in the range from 10 to 300 mM.
In principle, inhibition of one or more phosphodiesterases of this type results in an increase of the cGMP concentration. Thus, the compounds are of interest for all therapies in which an increase in the cGMP concentration is considered to be beneficial.
The cardiovascular effects were investigated using SH rats and dogs. The substances were administered intravenously or orally.
The novel active compounds and their physiologically acceptable salts (for example hydrochlorides, maleates or lactates) can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration of from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration is carried out in a customary manner, preferably orally, transdermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or inhalatively.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of administration route, on the individual response towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
For human use, in the case of oral administration, doses of from 0.001 to 30 mg/kg, preferably of 0.01 mg/kg-10 mg/kg are administered. In the case of parenteral administration, it is good practice to use doses of 0.001 mg/kg--1⁄2 mg/kg.
The compounds according to the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practice. Depending on the kind of animal to be treated, the veterinary surgeon can determine the nature of use and the dosage.


STARTING MATERIALS
Example 1A
2-Cyclopentanoylamino-propionic acid





16.8 g (0.189 mol) of D,L-alanine and 41.98 g (0.415 mol) of triethylamine are initially charged in 200 ml of dichloromethane. At 0° C., 45.07 g (0.415 mol) of trimethylsilyl chloride are added dropwise, and the mixture is then stirred at room temperature for 1 h and then at 40° C. for 1 h. The solution is cooled to −10° C. and 25 g (0.189 mol) of cyclopentanecarbonyl chloride are added dropwise. The mixture is stirred at −10° C. for 2 h and at room temperature for 1 h. With ice-cooling, 100 ml of water are added, and the mixture is then stirred for 10 min and the resulting precipitate is filtered off with suction. The precipitate is washed with 300 ml of water and then with 300 ml of diethyl ether and subsequently dried at 60° C.
Yield: 25.8 g (73.9% of theory) 1H-NMR (CD3OD): 1.35 (d, 3H); 1.5-1.9 (m, 8H); 2.7 (quin, 1H); 4.5 (quar., 1H):
Example 2A
2-Cyclopentanoylamino-butyric acid





10.31 g of 2-aminobutyric acid (100 mmol) and 22.26 g (220 mmol) of triethylamine are dissolved in 100 ml of dichloromethane, and the solution is cooled to 0° C. 23.90 g (220 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40° C. for 1 hour. After cooling to −10° C., 13.26 g (100 mmol) of cyclopentanecarbonyl chloride are added dropwise, and the resulting mixture is stirred at −10° C. for 2 hours and at room temperature for 1 hour.
With ice-cooling, 50 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The mixture is diluted with water and dichloromethane and the resulting precipitate is filtered off with suction: 11.1 g (55%) of a colourless solid. The dichloromethane phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is stirred with toluene and the precipitate is filtered off with suction: 5.75 g (28%) of a colourless solid:
200 MHz 1H-NMR (DMSO-d6): 0.88 (t, 3H); 1.61 (m, 10H); 2.66 (m, 1H); 4.09 (hex., 1H); 7.97 (d, 1H); 12.44 (s, 1H).
Example 3A
2-(2-Ethyl)-butanoylaminopropionic acid





24.5 g (0.275 mol) of D,L-alanine are initially charge in 250 ml of dichloromethane, and 61.2 g (0.605 mol) of triethylamine are added. The mixture is cooled to 0° C. and 65.7 g (0.605 mol) of trimethylsilyl chloride are added. The mixture is stirred at room temperature for 1 hour and at 40° C. for 1 hour. The mixture is cooled to −10° C., and 37 g (0.275 mol) of 2-ethylbutyryl chloride are added dropwise. The mixture is stirred at −10° C. for 2 hours and at room temperature overnight. The mixture is cooled in an ice-bath and 150 ml of water are added dropwise. 50 g (1.25 mol) of NaOH dissolved in 100 ml of water, are added, and the aqueous phase is separated off and concentrated. The residue is again taken up in water and acidified with concentrated hydrochloric acid, the aqueous solution is extracted repeatedly with dichloromethane and the organic phase is dried over Na2SO4 and concentrated.
Yield: 43.55 g (84.6% of theory) 200 MHz 1H-NMR (CDCl3): 0.91 (t, 6H); 1.5 (d, 3H); 1.52-1.73 (m, 4H); 1.99 (m, 1H); 4.61 (p, 1H); 6.25 (d, 1H); 6.76 (bs, 1H).
Example 4A
2-(2-Ethyl)-octanoylamino-propionic acid





18.6 g (0.211 mol) of D,L-alanine and 46.6 g (0.41 mol) of triethylamine are initially charged in 300 ml of dichloromethane. at 0° C., 50.09 g (0.461 mol) of trimethylsilyl chloride are added dropwise, and the mixture is stirred at room temperature for 1 h and then at 40° C. for 1 h. The solution is cooled to −10° C., and 40 g (0.21 mol) of 2-ethyloctanoyl chloride in 50 ml of dichloromethane are added dropwise. The mixture is stirred at room temperature overnight, and 100 ml of water are then added dropwise with ice-cooling, and the mixture is stirred for another 10 minutes. The phases are separated, the aqueous phase is extracted twice with in each case 100 ml of dichloromethane and the combined organic phases are dried over sodium sulphate and evaporated under reduced pressure. The residue is recrystallized from toluene by adding n-hexane and dried at 60° C.
Yield: 3.9 g (78.2%) 1H-NMR (CDCl3): 0.9 (m, 6h); 1.25 (pseudo s, 8H); 1.45 (d, 3H); 1.4-1.7 (m, 4H); 2.0 (m, 1H); 4.6 (quin. 1H); 6.1 (d, 1H).
Example 5A
2-Hexanoylamino-propionic acid





The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 24.93 g (0.185 mol) of hexanoyl chloride. The product crystallizes from toluene/n-hexane.
Yield: 33 g (95.2%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.2-1.4 (m, 7H); 1.6 (quin, 2H); 2.2 (t, 2H); 4.35 (quin, 1H).
Example 6A
2-Octanoylamino-propionic acid





The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 30.12 g (0.185 mol) of octanoyl chloride. The product crystallizes from toluene/n-hexane.
Yield: 34.3 g (86%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.2-1.4 (m, 11H); 1.6 (quin. 2H); 2.2 (t, 2H); 4.35 (quin. 1H).
Example 7A
2-Heptanoylamino-propionic acid





30 g (291 mmol) of methyl D,L-alaninate hydrochloride and 64.77 g (640 mmol) of triethylamine are initially charged in 300 ml of dry methylene chloride, at 0° C. 43.24 g (291 mmol) of heptanoyl chloride in 50 ml of methylene chloride are added dropwise. The mixture is allowed to warm to room temperature and stirred at this temperature for 2 h. The precipitate is filtered off, and the methylene chloride phase is extracted with saturated sodium bicarbonate solution and with saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is dissolved in 300 ml of methanol. 300 ml of water, in which 46.55 g (1164 mmol) of sodium hydroxide are dissolved, is added to this solution, and the mixture is stirred at RT for 2 h. The mixture is filtered, the methanol is removed using a rotary evaporator and the aqueous phase that remains is acidified with conc. Hcl to pH 1-2. The precipitated product is filtered off and dried. A second product fraction is obtained by extracting the aqueous phase with ethyl acetate.
Yield: 50 g (85.4%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.2-1.4 (m, 9H); 1.6 (quin., 2H); 2.2 (t, 2H); 4.38 (quar., 1H).
Example 8A
2-Decanoylamino-propionic acid





The preparation is carried out analogously to the procedure of Example 7A using 19.0 g (184 mmol) of methyl D,L-alaninate hydrochloride and 35.14 g (184 mmol) of decanoyl chloride.
Yield: 37.3 g (83.2%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.2-1.4 (m, 15H); 1.6 (m, 2H); 2.2 (t, 2H); 4.35 (quar., 1H).
Example 9A
2-(2-n-Propyl)-pentanoylamino-propionic acid





The preparation is carried out analogously to the procedure of Example 7A using 20.94 g (150 mmol) of methyl D,L-alaninate hydrochloride and 24.4 g (150 mmol) of 2-n-propylpentanoyl chloride.
Yield: 21.7 g (88.9%) 1H-NMR (CD3OD): 0.9 (t, 6H); 1.2-1.4 (m, 9H); 1.55 (m, 2H); 2.25 (m, 1H); 4.4 (quar., 1H).
Example 10A
2-Cycloheptanoylamino-propionic acid





The preparation is carried out analogously to the procedure of Example 7A using 20 g (143 mmol) of methyl D,L-alaninate hydrochloride and 23.02 g (143 mmol) of cycloheptanoyl chloride.
Yield: 16 g (52.4%) 1H-NMR (CD3OD): 1.35 (d, 3H); 1.45-1.65 (m, 8H); 1.7-1.95 (m, 4H); 2.35 (m, 1H); 4.25 (quar., 1H).
Example 11A
2-Ethoxy-benzonitrile





25 g (210 mmol) of 2-hydroxybenzonitrile, 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone are refluxed overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.
200 MHz 1H-NMR (DMSO-d6): 1.48 (t, 3H); 4.15 (quart., 2H); 6.99 (dt, 2H); 7.51 (dt, 2H).
Example 12A
2-Ethoxy-benzamidine hydrochloride





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 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until evolution of gas has ceased. 29.44 g (200 mmol) of 2-ethoxybenzonitrile are added, and the reaction mixture is then stirred at 80° C. (bath) overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction and the filter residue is 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. This gives 30.4 g (76%) of a colourless solid.
200 MHz 1H-NMR (DMSO-d6): 1.36 (t, 3H); 4.12 (quart., 2H); 7.10 (t, 1H); 7.21 (d, 1H); 7.52 (m, 2H); 9.30 (s, broad, 4H).
Example 13A
2-Propoxybenzonitrile





75 g (630 mmol) of 2-hydroxybenzonitrile, 174 g (1.26 mol) of potassium carbonate and 232.3 g (1.89 mol) of n-propyl bromide in 11 of acetone are refluxed overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure.
B.p.: 89° C. (0.7 mbar) Yield: 95.1 g (93.7% of theory)
Example 14A
2-Propoxybenzamidine hydrochloride





21.41 g (400 ml) of ammonium chloride are suspended in 400 ml of toluene and cooled to from 0 to 5° C. 200 ml of a 2M solution of triethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until evolution of gas has ceased. 32.2 g (200 mmol) of 2-propoxybenzonitrile are added, and the reaction mixture is then stirred at 80° C. (bath) overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 300 g of silica gel and 2.85 ml of ice-cold chloroform and stirred for 30 minutes. The mixture is filtered off with suction and the filter residue is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is stirred with 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 and filtered off with suction. This gives 22.3 g (52%) of product.
200 MHz 1H-NMR (CD3OD): 1.05 (t, 3H); 1.85 (sex, 2H); 4.1 (t, 2H); 7.0-7.2 (m, 2H); 7.5-7.65 (m, 2H).
Example 15A
2-(2-Ethoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





19.9 g (0.1 mol) of 2-cyclopentanoylamino-propionic acid (Example 1A), 24 ml of pyridine and 0.5 g of 4-dimethylaminopyridine are refluxed in 100 ml of absolute tetrahydrofuran, and 27.27 g (0.2 mol) of ethyl oxalyl chloride are added dropwise. The mixture is boiled at reflux for 90 minutes, cooled and put into 200 ml of ice-water. The mixture is extracted 3 times with ethyl acetate and the combined ethyl acetate phases are dried over sodium sulphate and evaporated. The residue is taken up in 30 ml of methanol and, after addition of 4.75 g of sodium bicarbonate, refluxed for 2.5 h. The mixture is filtered off and the resulting methanolic solution of the α-keto ester is directly reacted further, without further purification.
With ice-cooling, 4.99 g (0.1 mol) of hydrazine monohydrate are added dropwise to a solution of 20 g (0.1 mol) of 2-ethoxy-benzamidine hydrochloride (Example 12A) in 120 ml of ethanol, and the mixture is stirred at room temperature for 10 minutes. The methanolic solution of the α-keto ester described above is added dropwise to the suspension, and the mixture is stirred at 70° C. for 4 h. Following filtration, the solution is evaporated, the residue is partitioned between dichloromethane and water and the organic phase is, after drying over sodium sulphate, evaporated.
The residue is taken up in 150 ml of 1,2-dichloroethane, and 17 ml of phosphorus oxychloride are added dropwise. The mixture is stirred under reflux for 2 h and then cooled, washed twice with saturated sodium bicarbonate solution and dried over sodium sulphate. The organic phase is evaporated and the residue is chromatographed over silica gel using the mobile phase dichloromethane/methanol 50:1. The product-containing fractions are combined and evaporated. The product can be crystallized from ethyl acetate/petroleum ether.
Yield: 7.1 g (20.9%), white solid 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-1.8 (m, 2H); 1.8-2.0 (m, 4H); 2.05-2.2 (m, 2H); 2.6 (s, 3H); 3.65 (quin., 1H); 4.2 (quar, 2H); 7.1 (t, 1H); 7.15 (d, 1H); 7.5 (t, 1H); 7.7 (d, 1H).
Example 16A
2-(2-Ethoxyphenyl)-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 8.77 g (44 mmol) of 2-cyclopentanoylamino-butyric acid (Example 2A) and 8.83 g (44 mmol) of 2-ethoxy-benzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase cyclohexane/ethyl acetate (6:4).
Yield: 0.355 g (6.7%), white solid 1H-NMR (CDCl3): 1.32 (t, 3H); 1.57 (t, 3H); 1.94 (m, 8H); 3.03 (quar, 2H); 3.64 (quin, 1H); 4.27 (quar, 2H), 7.06 8d, 1H); 7.12 (t, 1H); 7.50 (t, 1H); 8.16 (dd, 1H); 9.91 (s, 1H).
Example 17A
2-(2-Propoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 8.33 g (45 mmol) of 2-cyclopentanoylamino-propionic acid (Example 1A) and 9.65 g (45 mmol) of 2-propoxybenzamidine hydrochloride (Example 14A). The product is purified by silica gel chromatography using the mobile phase dichloromethane/methanol (50:1). The product can be crystallized from ethyl acetate/petroleum ether.
Yield: 1.82 g (11.5%), white solid 1H-NMR (CDCl3): 1.15 (t, 3H); 1.7 (m, 2H); 1.95 (m, 4H); 2.15 (m, 2H); 2.65 (s, 3H); 3.65 (quin, 1H); 4.15 (t, 2H); 7.05 (d, 1H); 7.1 (t, 1H); 7.5 (td, 1H); 8.2 (dd, 1H).
Example 18A
2-(2-Ethoxyphenyl)-5-methyl-7-(2-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 21.45 g (0.1 mol) of 2-(2-ethyl)-butyrylamino-propionic acid (Example 3A) and 20.6 g (0.1 mol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase dichloromethane/methanol 60:1.
Yield: 7.22 g (21.3%) 200 MHz 1H-NMR (CDCl3): 0.87 (t, 6H); 1.57 (t, 3H); 1.88 (m, 4H); 2.67 (s, 3H); 3.28 (m, 1 h); 4.28 (q, 2H); 7.05 (d, 1H); 7.13 (dt, 1H); 8.15 (dd, 1H).
Example 19A
2-(2-Ethoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 10.95 g (45 mmol) of 2-(2-ethyl)octanoylamino-propionic acid (Example 4A) and 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase dichloromethane/methanol 100:1.
Yield: 2.76 g (15.5%), yellow oil 1H-NMR (CDCl3): 0.75-0.9 (m, 6H); 1.1-1.4 (m, 8H); 1.5 (t, 3h); 1.8-2.05 (m, 4h); 2.7 (s, 3H); 3.4 (quin, 1H); 4.3 (t, 2H); 7.05-7.2 (pseudo quar 2h); 7.5 (td, 1H); 8.2 (dd, 1H); 10.4 (broad, 1H).
Example 20A
2-(2-Propoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 10.95 g (45 mmol of 2-(2-ethyl)-octanoylamino-propionic acid (Example 4A) and 9.66 g (45 mmol) of 2-propoxybenzamidine hydrochloride (Example 14A). The product is purified by silica gel chromatography using the mobile phase dichloro-methane/methanol 60:1.
Yield: 3.7 g (20%), yellow oil 1H-NMR (CDCl3): 0.75-0.9 (m, 6H); 1.15 (t, 3h); 1.1-1.35 (m, 8H); 1.75-2.1 (m, 6h); 2.7 (s, 3H); 3.4 (quin, 1H); 4.2 (t, 2H); 7.05-7.2 (pseudo quar, 2H); 7.5 (td, 1H), 8.2 (dd, 1H); 10.2 (broad, 1H).
Example 21A
2-(2-Ethoxyphenyl)-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 9.36 g (50 mmol of 2-hexanoylamino-propionic acid (Example 5A) and 10.1 g (50 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase dichloromethane/methanol 50:1.
Yield: 3.1 g (18.3%), oil 1H-NMR (CD3OD): 0.9 (t, 3H); 1.3-1.4 (m, 4h); 1.45 (t, 3H); 1.8 (quin, 2H); 2.1 (s, 3H); 3.0 (t, 2H); 4.2 (quar, 2H); 7.1 (t, 1H); 7.15 (d, 1H); 7.5 (td, 1H); 7.7 (dd, 1H).
Example 22A
2-(2-Ethoxyphenyl)-5-methyl-7-heptyl-3H-imdazo-[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 14.7 g (68.1 mmol) of 2-octanoylamino-propionic acid (Example 6A) and 13.66 g (68.1 mmol) of 2-ethoxybenzamidine hdyrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase dichloromethane/methanol 50:1.
Yield: 4.65 g (18.5%), oil 1H-NMR (CD3OD): 0.85 (t, 3H); 1.2-1.4 (m, 8H); 1.45 (t, 3H); 2.8 (quin, 2H); 2.6 (s, 3H); 3.0 (t, 2H); 4.2 (quar, 2H); 7.1 (t, 1H); 7.2 (d, 1H); 7.55 (td, 1H), 7.7 (dd, 1H).
Example 23A





The preparation is carried out analogously to the procedure of Example 15A using 14.1 g (70 mmol) of 2-heptanoylamino-propionic acid (Example 7A) and 14.05 g (70 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase petroleum ether/ethyl acetate 1:1.
Yield: 3.5 g (14.1%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.3-1.45 (m, 6H); 1.4 (t, 3H); 1.7-1.9 (m, 2H); 2.15 (s, 3H); 3.1 (t, 2H); 4.2 (quar., 2H); 7.1 (t, 1H); 7.15 (d, 1H); 7.05 (td, 1H); 7.7 (dd, 1H).
Example 24A
2-(2-Ethoxyphenyl)-5-methyl-7-n-3H-imidazo[5,1-f]-[1,2,4-]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 17.0 g (70 mmol) of 2-decanoylamino-propionic acid (Example 8A) and 14.05 g (70 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase petroleum ether/ethyl acetate 1:1.
Yield: 3.5 g (14.1%) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.3-1.45 (m, 6H); 1.4 (t, 3H); 1.7-1.9 (m, 2H); 2.15 (s, 3H); 3.1 (t, 2H); 4.2 (quar., 2H); 7.1 (t, 1H); 7.15 (d, 1H); 7.05 (td, 1H), 7.7 (dd, 1H).
Example 24B
2-(2-Ethoxyphenyl)-5-methyl-7-n-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 17.0 g (70 mmol) of 2-decanoylamino-propionic acid (Example 8A) and 14.05 g (70 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase methylene chloride/methanol 50:1. The product can then be crystallized from petroleum ether.
Yield: 4.64 g (16.7%) 1H-NMR (CD3OD): 0.85 (t, 3H); 1.2-1.4 (m, 12H), 1.45 (t, 3H); 1.86 (quin., 2H); 2.6 (s, 3H); 3.0 (t, 2H); 4.2 (quar., 2H); 7.05 (t, 1H); 7.15 (d, 1H); 7.5 (td, 1H); 7.7 (dd, 1H).
Example 25A
2-(2-Ethoxyphenyl)-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 10.72 g (49.8 mmol) of 2-(2-n-propyl)-pentanoylamino-propionic acid (Example 9A) and 10.0 g (49.8 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase methylene chloride/methanol 100:1, then 50:1. The product can be recrystallized from diethyl ether.
Yield: 1.8 g (9.8%) M.p.: 150° C.
Example 26A
2-(Ethoxyphenyl)-5-methyl-7-cycloheptyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 15A using 14.9 g (70 mmol) of 2-cycloheptanoylamino-propionic acid (Example 10A) and 14 g (70 mmol) of 2-ethoxybenzamidine hydrochloride (Example 12A). The product is purified by silica gel chromatography using the mobile phase methylene chloride/methanol 10:1, and then 50:1.
Yield: 5.35 g (20.9%) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.6-2.0 (m, 10H); 2.1-2.2 (m, 2H); 2.7 (s, 3H); 3.65 (quin., 1H); 4.2 (quar., 2H); 7.1 (t, 1H); 7.2 (d, 1H); 7.6 (td, 1H); 7.75 (dd, 1H).
Example 27A
4-Ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





At 0° C., 7.0 g (20.7 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 15A) are added carefully to 24.1 g (207 mmol) of chlorosulphuric acid. The mixture is allowed to warm to room temperature and stirred overnight. The solution is carefully added to 200 ml of ice-water and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is distilled off under reduced pressure. The sulphonyl chloride is dried under reduced pressure and reacted further to the sulphonamides without further purification.
Yield: 7.95 g (88%), white foam 1H-NMR (CDCl3): 1.6 (t, 3H); 1.7 (m, 2H); 1.95 (m, 4H); 2.15 (m, 2H); 2.65 (s, 3H); 3.71 (quin, 1H); 4.4 (quar, 2H); 7.25 (d, 1H); 8.2 (dd, 1H); 8.7 (d, 1H); 9.9 (s, 1H).
Example 28A
4-Ethoxy-3-(5-ethyl-4-oxo-7-cyclopentyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 0.34 g (0.96 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-cyclopentyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 16A). This gives 0.43 g (98%) of sulphonyl chloride as a colourless foam which is directly reacted further.
Example 29A
4-Propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 0.7 g (2 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo-[5,1-f][12,4]triazin-4-one (Example 17A). This gives 0.8 g (89.3%) of sulphonyl chloride as a white foam which is directly reacted further.
Example 30A
4-Ethoxy-3-(5-methyl-4-oxo-7-(2-ethylpropyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 7.23 g (0.12 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylpropyl)-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 18A). This gives 8.56 g (91.9%) of sulphonyl chloride as a white solid which is directly reacted further.
Example 31A
4-Ethoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-imidazo[5,1f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 5.6 g (14.1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 19A). This gives 3.7 g (52.9%) of sulphonyl chloride as a slightly yellow foam which is directly reacted further.
Example 32A
4-Propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 1.4 g (3.41 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo-[5,1-f]-[1,2,4]-triazin-4-one (Example 20A). This gives 1.4 g (80.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Example 33A
4-Ethoxy-3-(5-methyl-4-oxo-7-pentyl-3H-imidazo-[5,1f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.88 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 21A). This gives 0.3 g (77.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Example 34A
4-Ethoxy-3-(5-methyl-4-oxo-7-heptyl-3H-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Example 35A
4-Ethoxy-3-(5-methyl-4-oxo-7-n-hexyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.84 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-hexyl-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 23A) and 0.98 g (8.4 mmol) of chlorosulphuric acid. This gives 300 mg (78.7%) of sulphonyl chloride which is directly reacted further.
Example 36A
4-Ethoxy-3-(5-methyl-4-oxo-7-n-nonyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 400 mg (1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-nonyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 24A) and 1.18 g (10 mmol) of chlorosulphuric acid. This gives 402 mg (80.1%) of sulphonyl chloride which is directly reacted further.
Example 37A
4-Ethoxy-3-(5-methyl-4-oxo-7-(2-n-propylbutyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 25A) and 950 mg (8.1 mmol) of chlorosulphuric acid. This gives 300 g (78.9%) of sulphonyl chloride which is directly reacted further.
Example 38A
4-Ethoxy-(5-methyl-4-oxo-7-cycloheptyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride





The preparation is carried out analogously to the procedure of Example 27A using 400 mg (1.1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-cycloheptyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 26A) and 1.27 g (11 mmol) of chlorosulphuric acid. This gives 402 mg (78.6%) of sulphonyl chloride which is directly reacted further.
PREPARATION EXAMPLES
Example 1
2-[2-Ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





60 mg (0.137 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f]-[1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane. 30 mg (0.343 mmol) of N-methylpiperazine are added, and the mixture is stirred at room temperature overnight. The mixture is washed twice with saturated ammonium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by silica gel flash chromatography (dichloro-methane/methanol 50:1).
Yield: 52 mg (75.6%) Rf=0.52 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.6-1.75 (m, 2H); 1.8-2.0 (m, 4H); 2.05-2.2 (m, 2H); 2.3 (s, 3H); 2.5-2.55 (m, 4H); 2.6 (m, 3H); 3.0 (s broad, 3H); 3.6 (quin, 1H); 4.3 (quar, 2H); 7.4 (d, 1H); 7.6 (dd, 1H); 8.0 (d, 1H).
Example 2
2-[2-Ethoxy-5-(N,N-bis-2-hydroxyethyl-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 800 mg (1.83 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 420 mg (4.03 mmol) of N,N-bis-2-hydroxyethylamine. This gives 530 mg (57.3%) of sulphonamide.
Rf=0.51 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-1.75 (m, 2H); 1.8-1.95 (m, 4H); 2.05-2.2 (m, 2H); 2.6 (s, 3H); 3.2-3.3 (m, 4H); 3.6 (quin 1H); 3.7 (t, 4H); 4.3 (quar, 2H); 7.35 (d, H); 8.0 (dd, 1H); 8.13 (d, 1H).
Example 3
2-[2-Ethoxy-5-(3-(4-morpholino)-propyl)-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 2.0 g (4.58 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f]-[1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 2.2 g (10.07 mmol) of 4-(3-aminopropyl)-morpholine. This gives 1.67 g (67%) of sulphonamide.
Rf=0.45 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.55-2.2 (m, 10H); 2.3-2.45 (m, 4H); 2.6 (s, 3H); 2.9 (t, 2H); 3.55-3.7 (m, 4H); 4.3 (quar. 2H); 7.3 (d, 1H); 8.0 (dd,); 8.1 (d, 1H).
Example 4
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 2.0 g (4.58 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 2.2 g (10.1 mmol) of N-(2-hydroxyethyl)piperazine. This gives 1.8 g (74.1%) of sulphonamide.
Rf=0.51 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.6-2.2 (m, 8H); 2.5 (t, 2H); 2.55-2.65 (m, 7H); 3.0-3.1 (m, 4H); 3.6 (t, +quin. 3H); 4.3 (quar. 2H); 7.35 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 5
2-[2-Ethoxy-5-(4-N-ethoxycarbonylmethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.23 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.504 mmol) of N-(carboethoxymethyl)piperazine. This gives 57 mg (43.5%) of sulphonamide.
Rf=0.53 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.25 (t, 3H); 1.45 (t, 3H); 1.65-2.2 (m, 8H); 2.5 (s, 3H); 2.6-2.7 (m, 4H); 3.0-3.1 (m, 4H); 3.25 (s, 2H); 3.6 (quin., 1H); 4.15 (quar, 2h); 4.3 (quar, 2H); 7.35 (d, 1H); 7.95 (dd, 1H); 8.0 (d, 1H).
Example 6
2-[2-Ethoxy-5-(4-N-carboxymethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





50 mg (0.084 mmol) of the ester from Example 5 and 10 mg (0.335 mmol) of sodium hydride are stirred at room temperature in 4 ml of methanol/water 3:1 for 30 minutes. The mixture is evaporated and the residue is purified by silica gel chromatography (mobile phase: methanol/dichloromethane 10:1).
Yield: 39 mg (85.4%) Rf=0.671 (CH2Cl2/MeOH 10:1+1% AcOH) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-2.2 (m, 2H); 2.1 (s, 3H); 2.15-2.25 (m, 4H); 3.05 (s, 2H); 3.05-3.15 (m, 4H); 3.6 (quin, 1H); 4.3 (quar, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.05 (d, 1H).
Example 7
2-[2-Ethoxy-5-(N-methyl-N-(2-dimethylaminoethyl)-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 60 mg (0.137 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 40 mg (0.343 mmol) of N-methyl-N-(2-dimethylamino-ethyl)-amine. This gives 52 mg (75.3%) of sulphonamide.
Rf=0.29 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-2.2 (m, 8H); 2.3 (s, 6H); 2.55 (t, 2H); 2.6 (s, 3H); 2.8 (s, 3H); 3.15 (t, 2H); 3.6 (quin, 1H); 4.3 (quar, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.1 (d, 1H).
Example 8
2-[2-Ethoxy-5-(4-ethoxycarbonylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 200 mg (0.458 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 160 mg (1 mmol) of methyl piperidine-4-carboxylate. This gives 190 mg (74.4%) of sulphonamide.
1H-NMR (CD3OD): 1.2 (t, 3H); 1.45 (t, 3H); 1.65-2.2 (m, 10H); 2.3 (m, 1H); 2.5-2.6 (m, 2H); 2.6 (s, 3H); 3.55-3.7 (m, 3H); 4.1 (quar, 2H); 4.3 (quar, 2H); 7.4 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 9
2-[2-Ethoxy-5-(4-carboxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





180 mg (0.323 mmol) of the ester from Example 8 and 50 mg (1.29 mmol) of sodium hydroxide are stirred at room temperature in 20 ml of methanol/water 3:1 for 30 minutes. 10 ml of water are added and the mixture is extracted once with dichloromethane. The aqueous phase is acidified using 2 n HCl and extracted twice with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and evaporated. The residue is recrystallized from diethyl ether.
Yield: 120 mg (70.2%) M.p.: 170° C. (decomp.)
Example 10
2-[2-Ethoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 60 mg (0.137 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 30 mg (0.302 mmol) of 4-hydroxymethylpiperidine. This gives 55 mg (77.7%) of sulphonamide.
Rf=0.46 (toluene/acetone 1:1)
Example 11
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 60 mg (0.137 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 60 mg (0.302 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethylamine. This gives 66 mg (80.9%) of sulphonamide.
Rf=0.64 (toluene/acetone 1:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.6-2.15 (m, 8H); 2.55 (s, 3H); 2.75 (s, 3H); 2.8 (t, 2H); 3.3 (t, 2H); 3.55 (quin, 1H); 3.8 (s, 6H); 4.25 (quar, 2H); 6.7-6.85 (m, 3H); 7.3 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 12
2-[2-Ethoxy-5-(4-ethoxyphenyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 70 mg (0.504 mmol) of 4-ethoxy-aniline. This gives 62 mg (50.4%) of sulphonamide which is purified by recrystallization from ethyl acetate/petroleum ether.
Yield: 62 mg (50.4%) M.p.: 245° C.
Example 13
2-[2-Ethoxy-5-(3-fluoro-4-methoxyphenyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 70 mg (0.5 mmol) of 3-fluoro-4-methoxyaniline. This gives 73 mg (58.9%) of sulphonamide which is purified by recrystallization from diethyl ether.
Yield: 73 mg (58.9%) M.p.: 180° C. (decomp.)
Example 14
2-[2-Ethoxy-5-(2-methoxyethyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 37.5 mg (0.05 mmol) of 2-methoxy-ethylamine. This gives 80 mg (73.2%) of sulphonamide.
Rf=0.47 (toluene/acetone 4:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-2.2 (m, 8H); 2.6 (s, 3H); 3.05 (t, 2H); 3.25 (s, 3H); 3.4 (t, 2H); 3.65 (quin, 1H); 4.3 (quin, 2H); 7.3 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H).
Example 15
2-[2-Ethoxy-5-(N-(4-morpholinyl)-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.5 mmol) of 4-aminomorpholine. This gives 108 mg (93.9%) of sulphonamide.
Rf=0.24 (toluene/acetone 4:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-2.2 (m, 8H); 2.6 (s, 3H); 2.9-3,0 (m, 4H); 3.65 (quin, 1H); 3.65-3.75 (m, 4H); 4.3 (quar, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.05 (d, 1H).
Example 16
2-[2-Ethoxy-5-(4-methoxybenzyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 400 mg (0.915 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 310 mg (2.29 mmol) of 4-methoxybenzylamine. This gives 260 mg (52.8%) of sulphonamide.
Rf=0.25 (toluene/acetone 4:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-1.75 (m, 2H); 1.8-1.95 (m, 4H); 2.1-2.2 (m, 2H); 2.55 (s, 3H); 3.63 (quin, 1H); 3.67 (s, 3H); 4.05 (s, 2H); 4.25 (quar, 2H); 6.75 (d, 2H); 7.1 (d, 2H); 7.25 (d, 1H); 7.9 (dd, 1H); 7.95 (d, 1H).
Example 17
2-[2-Ethoxy-5-(3-ethoxypropyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 300 mg (0.687 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 180 mg (1.717 mmol) of 3-ethoxy-propylamine. This gives 230 mg (66.5%) of sulphonamide.
Rf=0.19 (toluene/acetone) 1H-NMR (CD3OD): 1.1 (t, 3H); 1.45 (t, 3H); 1.65-2.2 (m 10H); 2.6 (s, 3H; 2.95 (t, 2H); 3.35-3.5 (m, 4H); 3.65 (quin, 1H); 4.25 (quar, 2H); 7.3 (d, 1H); 7.95 (dd, 1H); 8.1 (d, 1H).
Example 18
2-[2-Ethoxy-5-(3,4-dimethoxyphenyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 80 mg (0.5 mmol) of 3,4-dimethoxyaniline. This gives 70 mg (55.2%) of sulphonamide.
Rf=0.17 (toluene/acetone 4:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.75-1.95 (m, 6H); 2.15-2.3 (m, 2H), 2.7 (s, 3H); 3.65-3.8 (m, 7H); 4.2 (quar, 2H); 6.55 (dd, 1H); 6.7-6.8 (m, 2H); 7.3 (d, 1H); 7.9-8.0 (m, 2H).
Example 19
2-[2-Ethoxy-5-(2,3,4-trimethoxyphenyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.5 mmol) of 2,3,4-trimethoxyaniline. This gives 61 mg (45.7%) of sulphonamide.
Rf=0.25 (toluene/acetone 4:1) 1H-NMR (CD3OD): 1.4 (t, 3H); 1.65-1.95 (m, 6H); 2.05-2.2 (m, 2H); 2.55 (s, 3H); 3.5 (s, 3H); 36 (quin, 1H); 3.7 (s, 3H); 3.8 (s, 3H); 4.2 (quar, 2H); 6.7 (d, 1H); 7.15 (d, 1H); 7.2 (d, 1H); 7.8 (dd, 1H); 8.0 (d, 1H).
Example 20
2-[2-Ethoxy-5-(3-picolyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.5 mmol) of 3-picolylamine. This gives 50 mg (43%) of sulphonamide which is purified by recrystallization from ethyl acetate/diethyl ether.
M.p.: 128-130° C. (decomp.)
Example 21
2-[2-Ethoxy-5-(2-(2,6-dichlorophenyl)ethyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 400 mg (0.915 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 440 mg (2.29 mmol) of 2-(2,6-dichlorophenyl)ethylamine. This gives 380 mg (70.3%) of sulphonamide which is purified by recrystallization from ethyl acetate/diethyl ether.
M.p.: 202° C.
Example 22
2-[2-Ethoxy-5-(N-ethyl-N-(2-hydroxyethyl)-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.57 mmol) of N-ethyl-N-(2-hydroxyethyl)amine. This gives 57 mg (50.9%) of sulphonamide which is recrystallization from ethyl acetate/diethyl ether.
M.p.: 193° C.
Example 23
2-[2-Ethoxy-5-(2-(4-sulphonamidophenyl)-ethyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 110 mg (0.572 mmol) of 2-(4-sulphonamidophenyl)-ethylamine. This gives 67 mg (48.7%) of sulphonamide which is purified by recrystallization from ethyl acetate/diethyl ether.
M.p.: 141-143° C. (decomp.)
Example 24
2-[2-Ethoxy-5-(7-quinolinyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 400 mg (0.915 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 290.4 mg (2.014 mmol) of 7-aminoquinoline. This gives 264 mg (52.9%) of sulphonamide which is purified by recrystallization from ethyl acetate.
M.p.: 184° C.
Example 25
2-[2-Ethoxy-5-(1-(4-diethoxyphosphonylmethyl-piperidinyl)-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 120 mg (0.5 mmol) of 4-dimethoxyphosphonyl-methyl-piperidine. This gives 62 mg (42.6%) of sulphonamide.
1H-NMR (CD3OD): 1.25 (t, 6H); 1.45 (t, 3H); 1.5-2.2 (m, 15H); 2.3 (t, 2H); 2.6 (s, 3H); 3.5-3.8 (m, 3H); 4.05 (m, 4H); 4.8 (quar, 2H); 7.35 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 26
2-[2-Ethoxy-5-(1-(4-dimethoxyphosphonylmethyl-piperazinyl-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.229 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 100 mg (0.5 mmol) of (4-dimethoxyphosphonylmethyl)-piperazine. This gives 53 mg (38%) of sulphonamide.
Rf=0.57 (dichloromethane/methanol 10:1) 1H-NMR (CD3OD): 1.45 (t, 3H); 1.65-2.0 (m, 6H); 2.05-2.2 (m, 2H); 2.55 (s, 3H); 2.65-2.75 (m, 4H); 2.9 (d, 3H); 3.0-3.1 (m, 4H); 3.6 (quin, 1H); 3.7 (s, 3H); 3.75 (s, 6H); 4.3 (quar, 2H); 7.35 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 27
2-[2-Ethoxy-5-(methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one hydrochloride





220 mg (0.42 mmol) of 2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,-f][1,2,4]-triazin-4-one (Example 1) are suspended in 20 ml of diethyl ether and, after addition of 20 mg (0.462 mmol) of 1 molar ethereal HCl solution, stirred at room temperature for 30 minutes. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum.
Yield: 236 mg (99%)
Example 28
2-[2-Ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





0.42 g (0.92 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride are dissolved in 15 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of 4-dimethylaminopyridine, 0.28 g (2.76 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.395 g (80%) of a colourless solid.
200 MHz 1H-NMR (DMSO-d6): 1.21 (t, 3H); 1.32 (t, 3H); 1.79 (m, 8H); 2.13 (s, 3H); 2.48 (s, 4H); 2.86 (m, 6H); 4.21 (quart., 2H); 7.48 (m, 1H); 7.85 (m, 2H); 11.70 (s, 1H).
Example 29
2-[2-Ethoxy-5-N-ethyl-N-(2-hydroxyethyl)-amino-1-sulphonyl)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





In an analogous manner, starting from 1.35 g (3 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzene-sulphonyl chloride and 800 mg (9 mmol) of N-ethyl-N-(2-hydroxyethyl)-amine, 1.07 g (71%) of 2-[2-ethoxy-5-N-ethyl-N-(2-hydroxyethyl)-amino-1-sulphonyl)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.31 (dichloromethane/methanol=19:1) 200 MHz 1H-NMR (CDCl3): 1.20 (t, 3H); 1.32 (t, 3H); 1.61 (t, 3H); 1.95 (m, 9H); 2.41 (m, 1H); 3.02 (quart., 2H); 3.35 (m, 4H); 3.65 (m, 1H); 3.80 (m, 2H); 4.33 (quart., 2H); 7.15 (d, 1H); 7.95 (dd, 1H); 8.50 (d, 1H); 9.81 (s, 1H).
Example 30
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine)-1-sulphonyl)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





In an analogous manner, starting from 1.35 g (3 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride and 1.17 g (9 mmol) of 4-(2-hydroxyethyl)-piperazine, 1.21 g (74%) of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine)-1-sulphonyl)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.21 (dichloromethane/methanol=19:1) 200 MHz 1H-NMR (CDCl3): 1.31 (t, 3H); 1.60 (t, 3H); 1.96 (m, 9H); 2.58 (m, 7H); 3.02 (quart., 2H); 3.10 (m, 4H); 3.61 (m, 3H); 4.35 (quart., 2H); 7.19 (d, 1H); 7.89 (dd, 1H); 8.45 (d, 1H); 9.75 (s, 1H).
Example 31
2-[2-Ethoxy-5-(3-(4-morpholino)-propyl)-sulphonamido)-phenyl]-5-ethyl-3H-7-cyclopentyl-imidazo[5,1-j][1,2,4]triazin-4-one





In an analogous manner, starting from 1.35 g (3 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride and 1.30 g (9 mmol) of 4-(3-aminopropyl)-morpholine, 1.44 g (86%) of 2-[2-ethoxy-5-(3-(1-morpholino)-propyl)-sulphonamido)-phenyl]-5-ethyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.29 (dichloromethane/methanol=19:1) 200 MHz 1H-NMR (CDCl,): 1.31 (t, 3H); 1.60 (t, 3H); 2.02 (m, 12H); 2.46 (m, 8H); 3.02 (quart., 2H); 3.13 (t, 2H); 3.62 (m, 5H); 4.35 (quart., 2H); 7.15 (d, 1H); 7.89 (dd, 1H); 8.55 (d, 1H); 9.82 (s).
Example 32
2-[2-Propoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 28 mg (0.227 mmol) of 4-hydroxypiperidine. This gives 46 mg (80.5%) of sulphonamide.
Rf=0.53 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H);1.5-1.6 (m, 2H); 1.65-1.75 (m, 2H); 1.8-2.0 (m, 8H); 1.05-2.2 (m, 2H); 2.6 (s, 3H); 2.8-2.9 (m, 2H); 3.3-3.4 (m, 2H); 3.6-3.7 (m, 2H); 4.15 (t, 2H); 7.35 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 33
2-[2-Propoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.1111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 32.4 mg (0.249 mmol) of N-(2-hydroxyethyl)-piperazine. This gives 40 mg (73.6%) of sulphonamide which is purified by recrystallization from ethyl acetate/diethyl ether.
M.p.: 210° C.
Example 34
2-[2-Propoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 24.9 mg (0.249 mmol) of N-methylpiperazine. This gives 49 mg (95.4%) of sulphonamide.
Rf=0.49 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H); 1.65-2.2 (m, 2H); 2.3 (s, 3H); 2.45-2.55 (m, 4H); 2.6 (s, 3H); 3.0-3.1 (m, 4H); 3.6 (quin, 1H); 4.2 (t, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.0 (d, 1H).
Example 35
2-[2-Propoxy-5-(3-(4-morpholino)-propyl-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 36.7 mg (0.255 mmol) of 3-(4-morpholino)-propylamine. This gives 16 mg (28.1%) of sulphonamide.
Rf=0.41 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H); 1.6-2.2 (m, 12H); 2.3-2.45 (m, 6H); 2.6 (s, 3H); 2.95 (t, 2H); 3.6-3.7 (m, 5H); 4.15 (t, 2H); 7.35 (d, 1H); 8.0 (d, 1H); 8.1 (d, 1H).
Example 36
2-[2-Propoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 29.3 mg (0.255 mmol) of 4-hydroxymethylpiperidine. This gives 46 mg (85.1%) of sulphonamide.
Rf=0.46 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H); 1.65-2.0 (m, 13H); 2.05-2.15 (m, 2H); 2.3 (t, 2H); 2.6 (s, 3H); 3.4 (d, 2H); 3.65 (m, 1H); 3.8 (d, 2H); 4.2 (t, 2H); 7.4 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 37
2-[2-Propoxy-5-(N,N-bis-2-hydroxyethyl-sulphonamide)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 26.8 mg (0.255 mmol) of diethanolamine. This gives 30 mg (56.6%) of sulphonamide.
Rf=0.43 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H); 1.65-2.2 (m, 10H); 2.6 (s, 3H); 3.3 (m, 4H); 3.65 (quin, 1H); 3.7 (t, 4H); 4.2 (t, 2H); 7.35 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H).
Example 38
2-[2-Propoxy-5-(N-methyl-N-(2-dimethylaminoethyl)-sulphonamido)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 26 mg (0.255 mmol) of N-methyl-N-(2-dimethylaminoethyl)-amine. This gives 26 mg (49.3%) of sulphonamide.
Rf=0.3 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H);, 165-2.2 (m, 10H); 2.3 (s, 6H); 2.55 (t, 2H); 2.6 (s, 3H); 2.8 (s, 3h); 3.15 (t, 2H); 3.65 (quin., 1H); 4.2 (t, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.05 (d, 1H).
Example 39
2-[2-Propoxy-5-(4-ethoxycarbonylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.111 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-cyclopentyl-3,4-dihydro-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 48.7 mg (0.31 mmol) of ethyl 4-piperidinecarboxylate. This gives 80 mg (90.1%) of sulphonamide.
1H-NMR (CD3OD): 1.05 (t, 2H); 1.2 (t, 2H); 1.65-2.0 (m, 12H); 2.15-2.35 (m, 3H); 2.6 (td, 2H); 2.7 (s, 3H); 3.5-3.6 (, 2H); 3.75 (quin., 1H); 4.1 (quar., 2H); 4.2 (quar., 2H); 7.4 (d, 1H); 7.95 dd, 1H); 8.05 (d, 1H).
Example 40
2-[2-Propoxy-5-(4-carboxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





80 mg (0.14 mmol) of the ester from Example 39 are stirred at room temperature in a mixture of 5 ml of methanol and 1 ml of 4 n NaOH for 30 minutes. 10 ml of dichloromethane are added, the mixture is extracted with 10 ml of 2 n HCl solution and the organic phase is separated off, dried over sodium sulphate and evaporated. The residue is recrystallized from diethyl ether.
Yield: 50 mg (65.7%) Rf=0.47 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.05 (t, 3H); 1.65-2.0 (m, 12H); 2.2-2.35 (m, 3h); 2.6 (td, 2H); 2.7 (s, 3H); 3.55-3.6 (m, 2H); 3.75 (quin., 1H); 4.2 (t, 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.05 (d, 1H).
Example 41
2-[2-Ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





50 mg (0.114 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are initially charged in 5 ml of dichloromethane and a spatula tip of 4 dimethylaminopyridine is added, followed by 30 mg (0.342 mmol) of N-methylpiperazine. The mixture is stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated ammonium chloride solution, dried over sodium sulphate, concentrated and filtered through silica gel (methanol).
Yield: 45 mg (78.6% of theory) 200 MHz 1H-NMR (CDCl3): 0.85 (t, 6H); 1.63 (t, 3H); 1.85 (m, 4H); 2.39 (s, 3H); 2.65 (m, 7H); 3.17 (m, 5H); 4.35 (q, 2H); 7.18 (d, 1H); 7.88 (dd, 1H); 8.49 (d, 1H); 9.64 (bs, 1H).
Example 42
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 100 mg (0.221 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.662 mmol) of N-(2-hydroxyethyl)-piperazine, 99 mg (84.2% of theory) of 2-[2-ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.87 (t, 6H); 1.62 (t, 3H); 1.84 (m, 4H); 2.56-2.74 (m, 9H); 3.08-3.32 (m, 5H); 3.63 (t, 2H); 4.37 (q, 2H); 7.18 (d, 1H); 7.9 (dd, 1H); 8.5 (d, 1H); 9.67 (bs, 1H).
Example 43
2-[2-Ethoxy-5-(4-(2,2,2-trifluoroethyl)-piperazine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 100 mg (0.228 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 120 mg (0.69 mmol) of (2,2,2-trifluoroethyl)-piperazine, 72 mg (18.2% of theory) of 2-[2-ethoxy-5-(4-(2,2,2-trifluoroethyl)-piperazine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.87 (t, 6H); 1.63 (t, 3H); 1.89 (m, 4H); 2.71 (s, 3H); 2.8 (m, 4H); 2.97 (q, 2H); 3.1 (m, 4H); 3.25 (m, 1H); 4.38 (q, 2H); 7.19 (s, 1H); 7.89 (dd, 1H); 8.49 (d, 1H); 9.71 (bs, 1H).
Example 44
2-[2-Ethoxy-5-(1-(4-diethoxyphosphonylmethylpiperidinyl)-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imid-azo[5,1-f]-[1,2,4]-triazin-4-one





Analogously, using 100 mg (0.228 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 161 mg (0.683 mmol) of 4-diethoxyphosphonylmethyl-piperidine, 96.2 mg (66.2% of theory) of 2-[2-ethoxy-5-(1-(4-diethoxyphosphonylmethyl-piperidine)-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.86 (t, 6H); 1.3 (t, 6H); 1.38-2.02 (m, 14H); 2.35 (dt, 2H); 2.68 (s, 3H); 3.23 (m, 1H); 3.8 (d, 2H); 4.08 (m, 4H); 4.36 (q, 2H); 7.17 (d, 1H); 7.88 (dd, 1H); 8.49 (d, 1H); 9.7 (bs, 1H).
Example 45
2-[2-Ethoxy-5-(1-(4-monoethoxyphosphonylmethylpiperidinyl)-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





61.4 mg (96.2 μmol) of 2-[2-ethoxy-5-(1-(4-diethoxyphosphonylmethylpiperidinyl)-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are heated under reflux with 21.6 mg (0.385 mmol) of KOH powder in 5 ml of ethanol overnight. The mixture is concentrated, taken up in water, acidified with 1N hydrochloric acid and extracted three times with dichloromethane. The extracts are dried and concentrated.
Yield: 42 mg (71.6% of theory)
Example 46
2-[2-Ethoxy-5-(4-oxopiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imid-azo[5,1-f][1,2,4]triazin-4-one





Analogously using 300 mg (0.683 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 310 mg (2.05 mmol) of 4,4-dihydroxipiperidine hydrochloride, 18 mg (5.2% of theory) of 2-[2-ethoxy-5-(4-oxopiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Example 47
2-[2-Ethoxy-5-(3-hydroxypyrrolidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 100 mg (0.228 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 60 mg (0.683 mmol) of 3-hydroxypyrrolidine, 55 mg (49.1% of theory) of 2-[2-ethoxy-5-(3-hydroxy-pyrrolidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.85 (t, 6H); 1.61 (t, 3H); 1.72-2.1 (m, 7H); 2.69 (s, 3H); 3.22-3.55 (m, 5H); 4.35 (q, 2H); 4.45 (m, 1H); 7.18 (d, 1H); 7.99 (dd, 1H); 8.57 (d, 1H); 9.8 (bs, 1H).
Example 48
2-[2-Ethoxy-5-(N,N-diethyl-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 100 mg (0.228 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.683 mmol) of diethylamine, 78 mg (72.3% of theory) of 2-[2-ethoxy-5-(N,N-diethyl-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.87 (t, 6H); 1.2 (t, 6H); 1.62 (t, 3H); 1.88 (m, 4H); 2.69 (s, 3H); 3.3 (m, 5H); 4.35 (q, 2H); 7.14 (d, 1H); 7.96 (dd, 1H); 8.57 (d, 1H); 9.78 (bs, 1H).
Example 49
2-[2-Ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 100 mg (0.228 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.683 mmol) of 3-hydroxy-3-methoxymethylpyrrolidine, 89 mg (72.9% of theory) of 2-[2-ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.88 (t, 6H); 1.62 (t, 3H); 1.72-2.08 (m, 6H); 2.47 (s, 1H); 2.7 (s, 3H); 3.13-3.63 (m, 10H); 4.36 (q, 2H); 7.17 (d, 1H); 7.98 (dd, 1H); 8.57 d, 1H); 9.78 (bs, 1H).
Example 50
2-[2-Ethoxy-5-(N-2-methoxyethyl-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





Analogously, using 350 mg (0.797 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 180 mg (2.392 mmol) of methoxyethylamine, 251 mg (66% of theory) of 2-[2-ethoxy-5-(N-2-methoxyethyl-sulphonamide)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are obtained.
200 MHz 1H-NMR (DMSO-d6): 0.75 (t, 6H); 1.32 (t, 3H); 1.61-1.72 (m, 4H); 2.93 (q, 2H); 3.1 (m, 1H); 3.18 (s, 3H); 3.26-3.4 (m, 5H); 4.19 (q, 2H); 7.35 (d, 1H); 7.76 t, 1H); 7.86-7.96 (m, 2H); 11.7 (bs, 1H).
Example 51
2-[2-Ethoxy-5-(N-ethyl-N-(2-hydroxyethyl)-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





Analogously, using 400 mg (0.911 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 240 mg (2.734 mmol) of 2-(ethylamino)-ethanol, 261 mg (58.3% of theory) of 2-[2-ethoxy-5-(N-2-ethyl-N-(2-hydroxyethyl)-sulphonamide)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are obtained.
200 MHz 1H-NMR (DMSO-d6): 0.78 (t, 6H); 1.08 (t, 3H); 1.33 (t, 3H); 1.6-1.88 (m, 4H); 2.99-3.28 (m, 7H); 3.38 (m, 1H); 3.52 (q, 2H); 4.2 (q, 2H); 4.81 (t, 1H); 7.34 (d, 1H); 7.86-8.0 (m, 2H); 11.69 (bs, 1H).
Example 52
2-[2-Ethoxy-5-(N-(4-morpholinyl)sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





Analogously, using 400 mg (0.911 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 280 mg (2.734 mmol) of 4-aminomorpholine, 109 mg (21.1% of theory) of 2-[2-ethoxy-5-(N-(4-morpholinyl)sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are obtained.
200 MHz 1H-NMR (CDCl3): 0.88 (t, 6H); 1.63 (t, 3H); 1.85-2.28 (m, 4H); 2.88 (s, 3H); 3.05 (m, 4H); 3.45 (m, 1H); 3.76 (m, 4H); 4.42 (q, 2H); 7.2-7.35 (m, 2H); 7.96 (m, 1H); 8.45 (m, 1H); 10.23 (bs, 1H).
Example 53
2-[2-Ethoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





Analogously, using 400 mg (0.911 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 310 mg (2.734 mmol) of 4-hydroxymethylpiperidine, 270 mg (57.3% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
200 MHz 1H-NMR (DMSO-d6): 0.77 (t, 6H); 1.05-1.43 (m, 6H); 1.58-1.85 (m, 6H); 2.12-2.38 (m, 2H); 2.52 (s, 3H); 3.08 (m, 1H); 3.22 (t, 2H); 3.55-3.72 (m, 2H); 4.2 (q, 2H); 4.51 (t, 1H); 7.38 (d, 1H); 7.78-7.92 (m, 2H); 11.7 (bs, 1H).
Example 54
2-[2-Ethoxy-5-(3-(1-morpholino)-propyl)-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





In an analogous manner, starting from 0.44 g (1 mmol) of 3-(1-ethylpropyl)-5-methyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonyl chloride and 0.43 g (3 mmol) of 4-(3-aminopropyl)-morpholine 0.45 g (81%) of 2-[2-ethoxy-5-(3-(1-morpholino)-propyl)-sulphonamido)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.18 (dichloromethane/methanol=19:1) 200 MHz 1H-NMR (CDCl3): 1.31 (t, 3H); 1.61 (t, 3H); 1.87 (m, 14H); 2.66 (s, 3H); 3.00 (m 2H); 3.28 (m, 3H); 3.85 (m, 1H); 4.35 (quart., 2H); 7.17 (d, 1H); 7.90 (dd, 1H); 8.50 (d, 1H); 9.72 (s, 1H).
Example 55
2-[2-Ethoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-j][1,2,4]triazin-4-one





In an analogous manner, starting from 0.44 g (1 mmol) of 3-(7-(1-ethylpropyl)-5-methyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzene-sulphonyl chloride and 0.30 g (3 mmol) of 4-hydroxypiperidine, 0.33 g (65%) of 2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.25 (dichloromethane/methanol=19:1)
Example 56
2-[2-Ethoxy-5-(bishydroxyethylamino-1-sulphonyl)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo-[5,1-f][1,2,4]triazin-4-one





In an analogous manner, starting from 0.3 g (0.68 mmol) of 3-(7-(1-ethylpropyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzene-sulphonyl chloride and 0.22 g (2.01 mmol) of diethanolamine, 0.147 g (42%) of 2-[2-ethoxy-5-(bishydroxyethylamino-1-sulphonyl)-phenyl]-5-methyl-7-(1-ethylpropyl)-3H-imidazo-[5,1-f][1,2,4]triazin-4-one are obtained.
Rf=0.57 (dichloromethane/methanol=9:1) 200 MHz 1H-NMR (CDCl3): 0.98 (t, 6H); 1.62 (t, 3H); 1.89 (m, 4H); 2.67 (s, 3H); 3.23 (m, 3H); 3.36 (t, 4H); 3.90 (t, 4H); 4.36 (quart., 2H); 7.18 (d, 1H); 7.96 (dd, 1H); 8.55 (d, 1H); 9.68 (s, 1H).
Example 57
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 500 mg (1.01 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 290 mg (2.2 mmol) of 4-(2-hydroxyethyl)-piperazine. This gives 170 mg (28.6%) of sulphonamide.
Rf=0.56 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75-0.85 (2t, 6H); 1.1-1.35 (m, 8H); 1.45 (t, 3H); 1.65-1.95 (m, 4H); 2.0 (t, 2H); 2.55-2.65 (m, 7H); 3.0-3.1 (m, 4H); 3.3 (quin., 1H); 3.6 (t, 2H); 4.3 (quar., 2H); 7.4 (d, 1H); 7.95 (dd, 1H); 8.0 (d, 1H).
Example 58
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)sulphonamido-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 500 mg (1.01 mol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 433 mg (2.2 mmol) of N-methyl-N-2-(3,4-dimethoxyphenyl)-ethylamine. This gives 153 mg (23.2%) of sulphonamide.
Rf=0.78 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.7-0.5 (t, 6H); 1.0-1.35 (m, 8H); 1.45 (t, 2H); 1.6-1.95 (m, 4H); 2.6 (s, 3h); 2.75 (s, 3H); 2.8 (t, 2H); 3.15-3.35 (m, 3H); 3.75 (s, 6H); 4.3 (quar. 2H); 6.7-6.85 (m, 3H); 7.3 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 59
2-[2-Ethoxy-5-(3-(4-morpholino)-propyl-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 500 mg (1.01 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 320 mg (2.2 mmol) of 3-(4-morpholino)-propylamine. This gives 175 mg (28.7%) of sulphonamide.
Rf=0.58 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.5-0.9 (t, 6H); 1.1-1.35 (m, 8H); 1.45 (t, 3H); 1.65 (quin., 2H); 1.7-1.9 (m, 4H); 2.3-2.45 (m, 6h); 2.6 (s, 3H); 2.95 (t, 2H); 3.35 (m, 1H); 3.665 (2t, 4H); 4.3 (quar., 2h); 7.35 (d, 1H); 8.0 (dd, 1H); 8.1 (D, 1H).
Example 60
2-[2-Propoxy-5-(N-methyl-N(2-(3,4-dimethoxyphenyl)-ethyl)-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.25 mmol) of N-methyl-N-2-(3,4-dimethoxyphenyl)-ethylamine. This gives 45 mg (66%) of sulphonamide.
Rf=0.74 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 3H); 0.8 (t, 3h);, 105 (t, 3H);, 10-1.3 (m, 8H); 1.6-1.9 (m, 6h); 2.6 (s, 3H); 2.8 (s, 3H); 2.85 (t, 2H); 3.2-3.4 (m, 3H); 3.8 (s, 6H); 4.2 (t, 2H); 6.7-6.85 (m, 3H); 7.3 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 61
2-[2-Propoxy-5-(4-pyridyl-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 100 mg (0.196 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 22 mg (0.236 mmol) of 4-aminopyridine in the presence of 40 mg (0.4 mmol) of triethylamine. This gives 35 mg (31.4%) of sulphonamide which can be recrystallized from ethyl acetate/diethyl ether.
1H-NMR (CD3OD): 0.8 (2t, 6h); 1.0 (t, 3H); 1.05-1.35 (m, 8); 1.7-1.9 (m, 6H); 2.6 s, 3H); 3.35 (m, 1H); 4.15 (t, 2H); 7.1 (d, 1 h); 7.3 (d, 1H); 8.0 (m, 2H); 8.05 (dd, 1H); 8.1 (d, 1H).
Example 62
2-[2-Propoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 20 mg (0.2 mmol) of 4-hydroxypiperidine. This gives 43 mg (76.3%) of sulphonamide.
Rf=0.51 (CH2Cl2/MeOH 10:1)
1H-NMR (CDCl3): 0.7-0.85 (m, 6H); 1.05-1.3 (m, 11H); 1.35-2.05 (m, 14H); 2.65 (s, 3H); 2.85-3.0 (m, 2H); 3.15-3.35 (m, 3H); 3.6-3.7 (m, 1H); 4.2 (t, 2H); 7.1 (d, 1 h); 7.85 (dd, 1H); 7.95 (d, 1H); 9.8 (broad, 1H).
Example 63
2-[2-Propoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 26 mg (0.2 mmol) of N-(2-hydroxy-ethyl)-piperazine. This gives 13 mg (22%) of sulphonamide.
Rf=0.46 (CH2Cl2/MeOH 10:1) 1H-NMR (CDCl3): 0.7-0.85 (m, 6H); 1.0-1.3 (m, 11H); 1.6-2.0 (m, 6H); 2.55 (s, 3H); 2.5-2.7 (m, 4H); 3.0-3.1 (m, 3H); 3.15-3.3 (m, 1H); 3.6 (t, 2H); 4.2 (t, 2H); 7.15 (d, 1H); 7.7 (dd, 1H); 7.9 (d, 1H); 9.7 (broad, 1H).
Example 64
2-[2-Propoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 50 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 20 mg (0.2 mmol) of N-methyl-piperazine. This gives 42 mg (74.7%) of sulphonamide.
Rf=0.46 (CH2Cl2/MeOH 10:1) 1H-NMR (CDCl3): 0.75-0.9 (m, 6H); 1.1-1.35 (m, 11H); 1.6-2.1 (m, 10H); 2.4 (s, 3H); 2.65 (s, 3H); 2.6-2.75 (m, 2H); 3.1-3.4 (m, 4H); 4.25 (t, 2H); 7.2 (d, 1H); 7.9 (d, 1H); 8.5 (d, 1H); 9.7 (broad, 1H):
Example 65
2-[2-Propoxy-5-(4-ethoxycarbonylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 70 mg (0.138 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 43 mg of ethyl piperidinecarboxylate. This gives 55 mg (63.5%) of sulphonamide.
1H-NMR (CD3OD): 0.85 (t, 3H); 0.9 (t, 3H); 1.1 (t, 3H); 1.2 (t, 3H); 1.2-1.4 (m, 8H); 1.65-2.05 (m, 10H); 2.3 (m, 1H); 2.6 (td, 2H); 2.75 (s, 3H); 3.5 (quin., 1H); 3.6 (m, 2H); 4.1 (quar., 2H); 4.2 (t, 2H); 7.4 (d, 1H); 7.95-8.05 (m, 2H):
Example 66
2-[2-Propoxy-5-(4-carboxypiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





62 mg (0.098 mmol) of the ester from Example 65 are stirred at room temperature in 6 ml of 4 n NaOH/H2O (1:5) for 30 minutes. 20 ml of dichloromethane are added, the mixture is extracted with 2 n HCl solution, the organic phase is dried with sodium sulphate and the solvent is removed under reduced pressure.
Rf=0.44 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.85 (t, 3H); 0.9 (t, 3H); 1.05 (t, 3H); 1.2-1.4 (m, 8H); 1.7-2.05 (m, 10H); 2.75-2.9 (m, 1H); 2.6 (td, 2H); 2.75 (s, 3H); 3.5 (quin., 1H); 3.55-3.65 (m, 2H); 4.2 (t, 2H); 7.4 (d, 1H); 7.95-8.0 (m, 2H).
Example 67
2-[2-Propoxy-5-(3-(4-morpholino)-propyl)-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 52 mg (0.102 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 37 mg (0.255 mmol) of 3-(4-morpholino)-propylamine. This gives 45 mg (71.4% of sulphonamide.
Rf=0.41 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75-0.95 (m, 6H); 1.05 (t, 3H); 1.05-1.35 (m, 8H); 1.65 (t, 2H); 1.6-1.95 (m, 6H); 2.3-2.45 (m, 6H); 2.6 (s, 3H); 2.95 (t, 2H); 3.25 (m, 1H); 3.6-3.7 m, 4H); 4.2 (t, 2H); 7.35 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H).
Example 68
2-[2-Propoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 52 mg (0.102 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 29.3 mg (0.255 mmol) of 4-hydroxymethylpiperidine. This gives 45 mg (74.9%) of sulphonamide.
Rf=0.44 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75-0.9 (m, 6H); 1.05 (t, 3H); 1.0-1.45 (m, 10H); 1.7-1.95 (m, 8H); 2.35 (t, 2H; 2.6 (s, 3H); 3.2-3.4 (m, 2H); 3.8 (d, 2H); 4.2 (t, 2H); 7.4 (d, 1H); 7.9-8.0 (m, 2H).
Example 69
2-[2-Propoxy-5-(N,N-bis-2-hydroxyethyl-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 52 mg (0.102 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 27 mg (0.255 mmol) of diethanolamine. This gives 41 mg (69.5%) of sulphonamide.
Rf=0.36 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75-0.9 (m, 6H); 1.05 (t, 3H); 1.0-1.9 (m, 8H); 1.7-1.95 (m, 6H); 2.6 (s, 3H); 3.3 (t, 4H); 3.75 (t, 4H); 4.2 (t, 2H); 7.35 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H).
Example 70
2-[2-Propoxy-5-(N-methyl-N-(2-dimethylaminoethyl)-sulphonamido)-phenyl]-5-methyl-7-(2-ethylheptyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 52 mg (0.102 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-(2-ethylheptyl)-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 26 mg (0.255 mmol) of N-methyl-N-(2-dimethylaminoethyl)amine. This gives 42 mg (71.5%) of sulphonamide.
Rf=0.29 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75-0.85 (m, 6H); 1.05 (t, 3H); 1.1-1.35 (m, 8H); 1.7-1.95 (m, 6H); 2.3 (s, 6H); 2.55 (t, 2H); 2.6 (s, 3H); 2.8 (s, 3H); 3.15 (t, 2H); 3.3 (m, 1H); 4.2 (t, 2H); 7.4 (d, 1H); 8.0 (dd, 1H); 8.05 (d, 1H).
Example 71
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-sulphonamido)-phenyl]-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.342 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-pentyl-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 167 mg (0.854 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamine. This gives 195 mg (95.5%) of sulphonamide.
Rf=0.75 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 3H); 1.25-1.4 (m, 4H); 1.45 (t, 3H); 1.75 (quin., 2H); 2.55 (s, 3H); 2.75 (s, 3H); 2.8 (t, 2H); 2.95 (t, 2H); 3.75 (s, 6H); 4.25 (quar., 2H); 6.7 (dd, 1H); 6.8 (d, 1H); 6.85 (d, 1H); 7.3 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 72
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.342 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-pentyl-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 111 mg (0.854 mmol) of 2-hydroxyethyl-piperazine. This gives 95 mg (52.4%) of sulphonamide.
Rf=0.55 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.9 (t, 3H); 1.3-1.4 (m, 4H); 1.45 (t, 3H); 2.95 (t, 2H); 3.05-3.1 (m, 4H); 3.6 (t, 2H); 4.3 (quar., 2H; 7.4 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 73
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-sulphonamido)-phenyl]-5-methyl-7-heptyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.321 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-heptyl-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 140 mg (0.707 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamine. This gives 112 mg (55.7%) of sulphonamide.
Rf=0.74 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.7-0.9 (t, 6H), 1.2-1.35 (m, 8H); 1.45 (t, 3H), 1.75 (quin., wH); 2.6 (s, 3H); 2.75 (s, 3H); 2.8 (t, 2H); 2.95 (t, 2H); 3.8 (s, 6H); 4.3 (quar., 2H); 6.7 (dd, 1H); 6.8-6.9 (m, 2H); 7.3 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 74
2-[2-Ethoxy-5-(4-(2-hydroxyethyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-heptyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.321 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-heptyl-3,4-dihydro-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 92 mg (0.707 mmol) of 2-hydroxyethylpiperazine. This gives 160 mg (88.8%) of sulphonamide.
Rf=0.55 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.35 (t, 6H); 1.2-1.4 (m, 8H); 1.45 (t, 3H); 1.8 (quin., 2H); 2.5 (t, 2H); 3.0 (t, 2H); 3.05-3.1 (m, 4H); 3.3 (t, 2H); 3.6 (t, 2H); 4.3 (quar., 2H); 7.4 (d, 1H); 7.9 (dd, 1H); 8.0 (d, 1H).
Example 75
2-[2-Ethoxy-5-(4-(2-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-S-methyl-7-hexyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.33 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-n-hexyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.725 mmol) of 2-hydroxyethylpiperazine. This gives 90 mg (49.8%) of sulphonamide.
Rf=0.57 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 3H); 1.15-1.3 (m, 6H); 1.35 (t, 3H); 1.7 (quin., 2H); 2.4 (t, 2H); 2.5 (s, 3H) 2.5-2.55 (m, 4H); 2.9 (t, 2H); 2.95-3.0 (m, 4H); 3.5 (t, 2H); 2 (quar., 2H); 7.3 (d, 1H); 7.85 (dd, 1H), 7.9 (d, 11H).
Example 76
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)sulphonamido)-phenyl]-5-methyl-7-hexyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.33 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-n-hexyl-3,4-dihydro-imidazo-[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 140 mg (0.725 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamine. This gives 24.7%) of sulphonamide.
Rf=0.72 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 3H); 1.1-1.25 (m, 6H); 1.35 (t, 3H); 1.65 (quin., 2H); 2.5 (s, 3H); 2.65 (s, 3H); 2.7 (t, 2H); 2.85 (t, 2H); 3.65 (s, 6H); 4.15 (quar., 2H); 6.6-6.75 (m, 3H); 7.2 (d, 1H); 7.75 (dd, 1H); 7.9 (d, 1H).
Example 77
2-[2-Ethoxy-5-(4-(2-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-nonyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 200 mg (0.4 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-n-nonyl-3,4-dihydro-imidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 120 mg (0.89 mmol) of 2-hydroxyethyl-piperazine. This gives 85 mg (35.7%) of sulphonamide.
Rf=0.45 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 3H); 1.1-1.3 (m, 12H); 1.4 (t, 3H); 1.7 (quin., 2H); 2.4 (t, 2H); 2.5 (s, 3H); 2.5-2.6 (m, 4H); 2.9 (t, 2H); 2.95-3.05 (m, 4H); 3.5 (t, 2H); 4.3 (quar., 2H); 7.3 (d, 1H); 7.8 (dd, 1H); 7.9 (d, 1H).
Example 78
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl-ethyl)-sulphonamido)-phenyl]-5-methyl-7-nonyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 200 mg (0.4 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-n-nonyl-3,4-dihydro-imidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 170 mg (0.89 mmol) of N-methyl-N-(2-(3,4-dimethoxy)phenyl)-ethylamine. This gives 142 mg (52.8%) of sulphonamide.
Rf=0.74 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.7 (t, 3H); 1.1-1.3 (m, 12H); 1.4 (t, 3H); 1.7 (quin., 2H); 2.5 (s, 3H); 2.7 (s, 3H); 2.75 (t, 2H); 2.9 (t, 2H); 3.3 (t, 2H); 3.7 (s, 6H); 4.7 (quar., 2H); 6.6-6.8 (m, 3H); 7.2 (d, 1H), 7.7 (dd, 1H); 7.95 (d, 1H).
Example 79
2-[2-Ethoxy-5-(4-(2-hdyroxyethylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.32 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(2-n-propylbutyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.385 mmol) of 2-hydroxyethyl-piperazine. This gives 150 mg (83.3%) of sulphonamide.
Rf=0.62 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 0.75 (t, 6H); 1.1-1.25 (m, 4H); 1.4 (t, 3H); 1.6-1.7 (m, 2H); 1.75-1.85 (m, 2H); 2.45 (t, 2H); 2.5 (s, 3H); 2.5-2.55 (m, 4H); 3.0 (m, 4H); 3.4 (hept., 1H); 2.55 (t, 2H); 4.25 (quar., 2H); 7.35 (d, 1H); 7.85 (dd, 1H); 7.95 (d, 1H).
Example 80
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-sulphonamido)-phenyl]-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 150 mg (0.32 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(2-n-propylbutyl)-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonyl chloride and 80 mg (0.385 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamine. This gives 166 mg (82.6%) of sulphonamide.
M.p.: 131° C. (ethyl acetate/diethyl ether).
Example 81
2-[2-Ethoxy-5-(4-(2-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cycloheptyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 200 mg (0.43 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cycloheptyl-3,4-dihydro-imidazo[5,1-f]-[1,2,4]-triazin-2-yl-benzenesulphonyl chloride and 120 mg (0.946 mmol) of 2-hydroxyethyl-piperazine. This gives 158 mg (65.7%) of sulphonamide.
Rf=0.55 (CH2Cl2/MeOH 10:1)
Example 82
2-[2-Ethoxy-5-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-sulphonamido)-phenyl]-5-methyl-7-cycloheptyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one





The preparation is carried out analogously to the procedure of Example 1 using 300 mg (0.645 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-cycloheptyl-3,4-dihydro-imidazo[5,1-f]-[1,2,4]-triazin-2-yl-benzenesulphonyl chloride and 280 mg (1.42 mmol) of N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamine. This gives 256 mg (63.6%) of sulphonamide.
Rf=0.66 (CH2Cl2/MeOH 10:1) 1H-NMR (CD3OD): 1.45 (t, 2H); 1.5-1.7 (m, 9H); 1.7-2.0 (m,6H); 2.55 (s, 3H); 2.75 (s, 3H); 2.8 (t, 2H); 3.35 (t, 2H); 3.45 (quin., 1H); 3.7 (s, 6H); 4.25 (quar., 2H): 6.65-6.8 (m, 3H); 7.25 (d, 1H); 7.85 (dd, 1H); 8.0 (d, 1H).
The sulphonamides listed in the tables below were prepared by automatic parallel synthesis from the corresponding sulphonyl chlorides and the corresponding amines using one of the three standard procedures below.
The purity of the final product was determined by means of HPLC, and they were characterized by LC-MS. The number given in the column % (HPLC) is the content of the end product characterized by the molecular peak. Standard procedure A was used with amines having acidic functionalities, standard procedure B was used with amines having neutral functionalities, standard procedure C was used with amines having additional basic functionalities.
Compounds listed in the tables below and having optically a free nitrogen valency are, in principle, to be understood as —NH— radical.
Standard Procedure A:
Reaction of Amines Having Acidic Functionalities
0.05 mmol of amine, 0.042 mmol of sulphonyl chloride and 0.10 mmol of Na2CO3 are initially charged, and 0.5 ml of a mixture of THF/H2O is pipetted in by hand. After 24 h at room temperature, the mixture is admixed with 0.5 ml of 1 M H2SO4 solution and filtered through a two-phase cartridge (500 mg of Extrelut (upper phase)) and 500 mg of SiO2, mobile phase ethyl acetate). The product is obtained after concentrating the filtrate under reduced pressure.
Standard Procedure B:
Reaction of Amines Having Neutral Functionalities
0.125 mmol of amine are initially charged and 0.03 mmol of sulphonyl chloride as a solution in 1,2-dichloroethane is pipetted in by the synthesizer. After 24 h, the mixture is admixed with 0.5 ml of 1 M H2SO4 and filtered through a two-phase cartridge (500 mg of Extrelut (upper phase) and 500 mg of SiO2, mobile phase: ethyl acetate). The filtrate is concentrated under reduced pressure.
Standard Procedure C:
Reaction of Amines Having Basic Functionalities
0.05 mmol of amine are initially charged and 0.038 mmol of sulphonyl chloride as a solution in 1,2-dichloroethane and 0.05 mmol of triethylamine as a solution in 1,2-dichloroethane are pipetted in by the synthesizer. After 24 h, the solution is initially admixed with 3 ml of saturated NaHCO3 solution and the reaction mixture is filtered through a two-phase cartridge. The product is obtained after concentrating the filtrate under reduced pressure.
All reactions are monitored by thin-layer chromatography. If the reaction is not complete after 24 h at room temperature, the mixture is heated at 60° C. for a further 12 h and the experiment is subsequently terminated.










TABLE 1





Ex. No.
Structure
MW
% (HPLC)*


















83





505.6
76


84





583.71
89


85





491.57
56


86





570.76
60


87





539.66
87


88





569.69
88


89





567.67
82


90





555.66
91


91





569.69
77


92





553.66
54


93





551.73
62


94





609.73
60


95





537.66
88


96





477.59
97


97





611.74
52


98





533.65
85


99





602.11
NMR


100





543.62
88


101





546.69
82


102





528.68
82


103





530.65
77


104





583.71
91


105





540.69
58


106





541.63
38


107





559.69
60


108





594.74
88


109





548.67
61


110





636.82
85


111





504.66
67


112





506.63
57


113





562.74
84


114





531.68
61


115





475.61
90


116





588.73
82


117





573.69
52


118





505.64
92


119





487.54
>58


120





609.75
86


121





625.77
98


122





560.68
90


123





593.77
46


124





610.8
64


125





593.75
84


126





623.78
85


127





503.63
89


128





559.65
58


129





569.69
70


130





564.71
76


131





591.74
77


132





541.65
66


133





489.6
83


134





595.72
84


135





664.87
70


136





517.65
77


137





563.63
31


138





559.69
88


139





501.65
81


140





607.66
86


141





521.6
37


142





593.75
82


143





517.65
85


144





611.74
67


145





614.17
78


146





613.8
47


147





624.78
52


148





645.8
69


149





583.73
75


150





505.64
78


151





491.61
83


152





535.67
81









The yields are based on the molecular peaks determined by mass spectroscopy.













Ex. No.
Structure
MW
% HPLC*


















153





578.7
70


154





580.7
75


155





508.6
62


156





489.6
72


157





565.7
76


158





485.5
42


159





531.6
88


160





537.6
80


161





553.6
78


162





607.7
75


163





561.6
80


164





523.6
83


165





523.6
84


166





565.7
81


167





562.5
63


168





590.5
82


169





581.7
81


170





535.6
79


171





567.7
55


172





605.6
81


173





595.7
79


174





623.8
79


175





597.7
59


176





653.8
41


177





653.8
82


178





557.7
83


179





529.6
83


180





529.6
86


181





560.7
82


182





562.7
81


183





526.7
60


184





592.7
80


185





608.8
80


186





634.8
77


187





528.6
71


188





533.7
87


189





558.7
88


190





593.7
73


191





515.6
80


192





612.2
81


193





591.7
83


194





621.8
79


195





501.6
78


196





557.6
57


197





605.7
80


198





591.7
80


199





607.7
78


200





499.6
83


201





487.6
82


202





501.6
66


203





609.7
79


204





530.7
82


205





489.6
80


206





537.6
63


207





537.6
75


208





537.6
72


209





607.7
50


210





489.6
64


211





551.7
77


212





581.7
85


213





475.6
45


214





528.6
87


215





503.6
74


216





517.7
76


217





503.6
84


218





551.7
74


219





503.6
70


220





551.7
73


221





489.6
57


222





475.6
77


223





593.8
68


224





551.7
77


225





615.8
78


226





503.6
52


227





529.7
59


228





515.6
50


229





584.7
42


230





557.7
82


231





487.6
49


232





533.7
80


233





537.6
81


234





565.7
82


235





565.7
56


236





669.8
82


237





551.7
77


238





517.7
91





*The yields are based on the molecular peaks determined by mass spectroscopy. 






















MW




Ex. No.
Structure
[g/mol]
HPLC
Mz + H



















239





531,723
77
532


240





533,695
71
534


241





595,767
65
596


242





602,846
53
603


243





634,848
64
635


244





586,803
51
587


245





574,792
61
575


246





628,884
41
629


247





602,846
42
603


248





642,911
44
643


249





652,863
66
653


250





618,845
48
619


251





660,883
71
661


252





682,892
50
683


253





600,83
60
601


254





612,841
68
613


255





622,836
66
623


256





604,818
58
605


257





590,791
56
591


258





600,83
59
601


259





612,841
54
613


260





706,955
72
707


261





574,792
56
575


262





621,808
57
622


263





588,819
52
589


264





547,722
79
548


265





561,749
30
562


266





620,82
68
621


267





626,868
56
627


268





584,787
56
585


269





640,895
69
641


270





634,848
72
635


271





634,848
54
635


272





656,801
64
657


273





638,811
65
639


274





650,847
44
651


275





545,706
60
546


276





558,749
50
559


277





591,776
70
592


278





616,786
53
617


279





588,775
49
589


280





644,84
51
645


281





609,75323
55
610


282





581,73983
66
582


283





581,73983
63
582


284





595,76692
68
596


285





 5,76692
68
596


286





593,79461
70
594


287





609,79401
68
610


288





639,8205
63
640


289





658,84499
61
659


290





581,73983
59
582


291





551,71334
71
552


292





595,76692
69
596


293





609,79401
65
610


294





595,76692
56
596


295





665,85874
54
666


296





638,83577
64
639


297





581,73983
66
582


298





623,77747
63
624


299





611,76632
65
612


300





609,79401
61
610


301





595,76692
65
596


302





581,73983
71
582


303





581,73983
72
582


304





599,73026
69
600


305





639,8205
65
640


306





641,79281
68
642


307





658,66355
75
658


308





595,76692
72
596


309





579,76752
74
580


310





635,71112
69
636


311





586,15837
64
586


312





623,77747
55
624


313





623,8211
69
624


314





609,79401
72
610


315





609,79401
72
610


316





727,92766
65
728


317





623,8211
54
624


318





683,87408
68
684


319





653,84759
71
654


320





653,84759
68
654


321





664,91764
84
665


322





617,86062
60
618























Ex.

MW




No.
Structure
[g/mol]
HPLC
Mz + H



















323





650,84692
62
651


324





477,5869
87
478


325





505,6411
89
506


326





539,6586
88
540


327





567,7127
81
566


328





553,6857
81
554


329





553,6857
83
554


330





519,6681
93
520


331





579,7239
77
580


332





502,6404
86
503


333





489,598
83
490


334





523,6592
89
524


335





594,7822
85
595


336





553,6857
85
554


337





579,7675
80
580


338





591,6575
84
592


339





535,6675
89
536


340





504,6563
91
505


341





671,8193
79
672


342





530,6509
89
531


343





516,6238
85
517


344





637,7411
78
638


345





550,685
86
551


346





597,7392
83
598


347





636,6028
82
636


348





611,7663
78
612


349





567,7127
80
568


350





596,7545
82
597


351





594,7822
79
595


352





608,8093
84
609


353





566,728
82
567


354





594,7386
85
595


355





517,6522
85
518


356





560,6774
83
561


357





531,6793
84
532


358





517,6522
85
518


359





489,598
85
490


360





517,6522
84
518


361





593,751
81
594


362





623,7775
50
624


363





475,6146
90
476


364





583,7121
76
584


365





525,6315
69
526


366





539,6586
71
540


367





509,6321
56
510


368





523,6592
86
524


369





583,7121
80
584


370





525,6315
72
526


371





495,605
83
496


372





560,0765
52
560


373





511,6044
73
512


374





537,6863
81
538


375





538,6738
74
539


376





567,7127
74
568


377





566,6844
88
567


378





531,5858
82
532


379





537,6426
47
538


380





513,5954
83
514


381





544,0771
82
545


382





592,5492
72
593


383





580,7115
70
581


384





555,658
81
556


385





553,6857
80
554


386





539,6586
75
540


387





525,6315
86
526


388





530,05
80
531


389





525,6315
86
526


390





543,6219
76
544


391





563,6034
81
564


392





583,7121
79
584


393





585,6845
84
586


394





539,6586
80
540


395





477,5869
87
478


396





530,6509
91
531


397





503,6251
87
504


398





505,6411
90
506


399





530,6946
51
531


400





539,6586
74
540


401





532,6669
70
533


402





545,6655
79
546


403





539,6586
85
540


404





525,6315
81
526


405





564,495
90
565


406





564,495
60
565


407





611,7663
84
612


408





553,6857
79
554


409





567,7127
75
568


410





537,6863
80
538


411





551,7133
86
552


412





630,7908
37
631


413





553,6857
66
554


414





523,6592
82
524


415





588,1307
31
588


























HPLC



Ex.

MW
area % at



No.
Structure
[g/mol]
210 nm
Mz + H



















416





539,6586
77
540


417





565,7404
80
566


418





566,728
68
567


419





595,7669
84
596


420





594,7386
77
595


421





559,64
81
560


422





565,6968
42
566


423





541,6496
82
542


424





572,1313
85
572


425





620,6034
80
620


426





608,7657
84
609


427





583,7121
82
584


428





581,7398
77
582


429





567,7127
80
568


430





553,6857
82
554


431





558,1042
80
558


432





553,6857
85
554


433





571,6761
79
572


434





591,6575
83
592


435





613,7386
77
614


436





613,7386
82
614


437





567,7127
84
568


438





505,6411
85
506


439





558,7051
90
559


440





531,6793
87
532


441





533,6952
90
534


442





558,7487
75
559


443





576,7205
66
577


444





567,7127
77
568


445





560,7211
79
561


446





573,7197
76
574


447





567,7127
80
568


448





553,6857
83
554


449





592,5492
30
592


450





592,5492
43
592


451





609,750
78
610


452





551,670
74
552


453





565,697
65
566


454





535,670
80
536


455





549,697
79
550


456





671,759
83
672


457





551,670
69
552


458





521,643
80
522


459





586,115
34
586


460





537,643
76
538


461





563,724
67
564


462





564,712
73
565


463





593,751
79
594


464





592,723
72
593


465





557,624
78
558


466





563,681
44
564


467





539,634
67
540


468





570,115
75
570


469





618,587
65
618


470





606,750
69
607


471





581,696
80
582


472





579,724
76
580


473





565,697
72
566


474





551,670
78
552


475





556,088
67
556


476





551,670
79
552


477





569,660
77
570


478





589,642
62
590


479





611,723
66
612


480





611,723
86
612


481





565,697
80
566


482





503,625
85
504


483





556,689
88
557


484





529,663
81
530


485





531,679
86
532


486





574,705
33
575


487





565,697
61
566


488





558,705
47
559


489





571,704
59
572


490





565,697
70
566


491





551,670
65
552


492





590,533
46
590


493





590,533
83
590


494





530,65
82
531


495





489,60
49
490


496





537,64
63
538


497





537,64
44
538


498





537,64
72
538


499





607,73
50
608


500





489,60
64
490


501





551,67
70
552


502





551,67
77
552


503





581,70
85
582


504





475,57
45
476


505





503,63
74
504


506





517,65
76
518


507





503,63
59
504


508





551,67
74
552


509





503,63
70
504


510





551,67
73
552


511





489,60
57
490


512





489,60
44
490


513





475,57
42
476


514





593,75
68
594


























HPLC



Ex.

MW
area % at



No.
Structure
[g/mol]
210 nm
Mz + H



















515





551,67
77
552


516





615,75
78
616


517





503,63
52
504


518





529,66
59
530


519





515,64
50
516


520





584,74
42
585


521





557,67
82
558


522





487,58
30
488


523





533,65
60
534


524





537,64
81
538


525





565,70
82
566


526





565,70
56
566


527





669,80
82
670


528





551,67
77
552


529





517,65
91
518


530





597,7392
84
598


531





539,6586
74
540


532





553,6857
77
554


533





523,6592
93
524


534





537,6863
94
538


535





659,74
89
660


536





616,7637
80
617


537





539,6586
73
540


538





509,6321
92
510


539





574,1036
48
574


540





525,6315
75
526


541





551,7133
84
552


542





552,7009
75
553


543





581,7398
83
582


544





580,7115
80
581


545





545,6129
91
546


546





551,6697
54
552


547





527,6225
89
528


548





558,1042
83
558


549





606,5763
55
606


550





594,7386
83
595


551





569,6851
87
570


552





567,7127
79
568


553





553,6857
88
554


554





539,6586
88
540


555





554,0771
83
544


556





539,6586
93
540


557





557,649
88
558


558





577,6305
77
578


559





599,7115
81
600


560





599,7115
88
600


561





553,6857
89
554


562





491,614
92
492


563





517,6086
83
518


564





544,678
94
545


565





517,6522
94
518


566





519,6681
95
520


567





562,6934
74
563


568





553,6857
80
554


569





546,694
87
547


570





559,6926
73
560


571





553,6857
86
554


572





539,6586
90
540


573





578,5221
87
578


574





578,5221
92
578


575





501,6528
50
502


576





643,80875
76
644


577





533,6516
75
534


578





531,67929
88
532


579





517,6522
87
518


580





565,6968
84
566


581





593,75098
88
594


582





579,72389
74
580


583





579,72389
65
580


584





545,70638
85
546


585





697,85754
68
698


586





531,67929
52
532


587





556,68917
88
557


588





542,66208
78
543


589





663,77937
92
664


590





576,72322
85
577


591





653,80396
77
654


592





575,73287
91
576


593





517,6522
86
518


94





589,75996
90
590


595





571,74462
71
572


596





615,7982
92
616


597





593,75098
78
594


598





634,84752
76
635


599





630,81287
81
631


600





582,77104
82
583


601





570,75989
34
571


602





607,77807
82
608


603





591,73789
73
592


604





543,69044
79
544


605





598,72681
68
599


606





592,72547
42
593


607





529,66335
76
530


608





557,71753
88
558


609





543,69044
83
544


610





612,79753
64
613


611





585,72808
88
586


612





515,63626
81
516


613





543,69044
78
544


614





528,67862
30
529


615





489,64
84
490


616





631,80
88
632


617





521,64
87
522


618





519,67
89
520


619





505,64
94
506


620





553,69
90
554


621





581,74
85
582


622





567,71
85
568


623





567,71
86
568


624





533,70
85
534


625





685,85
84
686


626





519,67
83
520


627





544,68
92
545


628





530,65
82
531


629





651,77
89
652


630





564,71
87
565


631





641,79
87
642


632





563,72
85
564


633





505,64
88
506


634





577,75
96
578


635





559,73
79
560


636





603,79
88
604


637





581,74
83
582


638





622,84
90
623


639





618,80
85
619


640





570,76
60
571


641





558,75
40
559


642





595,77
90
596


643





579,73
87
580


644





531,68
91
532


645





586,72
69
587


646





580,71
78
581


647





517,65
86
518


648





545,71
82
546


649





531,68
86
532


650





600,79
57
601


651





573,72
82
574


652





503,63
83
504


653





531,68
83
532

## Claims

1. A method of treating hypertension, neuronal hypertonia, stable and unstable angina, peripheral and cardial vasculopathies, arrhythmiae, thromboembolic disorders, myocardial infarction, angina pectoris, peripheral circulation obstruction, restenoses after thrombolysis therapy, percutaneous transluminal coronary angioplasties or bypass, stroke, hypertrophy of the prostate and incontinence, comprising administering to a mammal an effective amount of a compound of the formula (I) 




in which
R1 represents s might-chain or branched alkyl having up to 4 carbon atoms, 
R2 represent straight-chain [lacuna] having at least 5 carbon atoms or branched alkyl having at least 3 carbon atoms, or 

represents cycloalkyl having 3 to 10 carbon atoms, 


R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 8 carbon atoms, or represent 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 mono- to trisubstituted by identical or different substituents from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 6 carbon atoms and/or by radicals of the formulae —SO3H, -(A)a-NR7R8, —O—CO—NR7′R8′, —S(O)b—R9, HN═SO—R9′, —P(O)(OR10)(OR11), 




 in which 
a and b are identical or different and represent a number 0 or 1, 
A represents a radical CO or SO2, 
R7, R7′, R8 and R8′ are identical or different and represent hydrogen, or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(SO2)c—NR12R13, 
in which 
c represents a number 0 or 1, 
R12 and R13 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or 

R7, R7′, R8 and R8′ represent straight-chain or branched alkoxy having up to 6 carbon atoms, or 
represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, aryl having from 6 to 10 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(CO)d—NR14R15, 
in which 
R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and 
d represents a number 0 or 1, or 

R7 and R8 and/or R7′ and R8′ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR16, 
in which 
R16 represents hydrogen, aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, 

R9 and R9′ are identical or different and represent aryl having 6 to 10 carbon atoms or benzyl, or represent straight-chain or branched alkyl having up to 4 carbon atoms, 
R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, 
and/or the alkyl chain listed above under R3/R4 is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 ring heteroatoms from the group consisting of S, N; O or a radical of the formula —NR17, where the alkyl chain way optionally also be attached via a ring nitrogen atom, 
in which 
R17 represents hydrogen, hydroxyl, formyl, trifluoroxyethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms, 


and where aryl and the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of nitro, halogen, —SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO2)e—R18R19, 
in which 
e represents a number 0 or 1, 
R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 6 carbon atoms, and/or 

R3 or R4 represent radicals of the formulae —NR20R21 or —(O)-E-NR22R23, 
in which 
R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or 
together with the nitrogen atom form a 5- or 6-membered saturated heterocycle having a further ring heterocycle from the group consisting of S and O or a radical —NR24, 
in which 
R24 has the meaning of R16 given above and is identical to or different from this meaning, 

E is a straight-chain alkylene group having up to 5 carbon atoms, 
R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning, and/or 

R3 or R4 represent radicals of the formulae 




 or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered partially unsaturated, saturated and unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N; O or a radical of the formula —NR25 which may optionally also be attached via a ring nitrogen atom, 
in which 
R25 has the meaning of R16 given above and is identical to or different from this meaning, or 
represents carboxyl formyl or straight-chain or branched acyl having up to 5 carbon atoms, 

and where cycloalkyl, aryl and/or the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and/or by groups of the formulae —SO3H, —O26, (SO2)cNR27R28, —P(O)(OR29)(OR30), 
in which 
R26 represents a radical of the formula 





 or 
 represents cycloalkyl having 3 to 7 carbon atoms, or hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen, 

f is a number 0 or 1, 
R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula —CO—NH2, 
R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 


and/or cycloalkyl, aryl and/or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or by groups of the formulae —SO2—R31, P(O)(OR32)(OR33) or NR34R35, 
in which 
R31 is hydrogen or has the meaning of R9 given above and is identical to or different from this meaning, 
R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 
R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or 
R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from rue group consisting of S and O or a radical of the formula —NR36, 
in which 
R36 has the meaning of R≠given above and is identical to or different from this meaning, or 


R3 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N, O or a radical of the formula —NR37, 
in which 
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cycloalkyl having 3to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms, 
R37 represents a radical of the formula —(CO)g-G, 
in which 
g represents a number 0 or 1, 
G represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to unsubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 6 carbon atoms, hydroxyl and trifluoromethyl, 


and the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally mono- to trisubstituted optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 6 carbon atoms and groups of the formulae —P(O)(OR38)(OR39) and —(CO)g)—NR40R41, 
in which 
R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 
g represents a number 0 or 1, and 
R40 and R41 are identical or different and have the meaning of R18 and R19 given above, 

and/or the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a radical of the formula —SO3H, —NR42R43 or P(O)OR44R45, 
in which 
R42 and R43 are identical 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, 
R44 and R45 are identical or different and have the meaning of R10 and R11 given above, 

and/or the alkyl is optionally substituted by benzyloxy or aryl having 6 to 10 carbon atoms which for its part way be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy or alkylthio having in cash case up to 6 carbon atoms, or by a group of the formula —NR42 ′R43′, 
in which 
R42′ and R43′ have the meaning of R42 and R43 given above and are identical to or different from this meaning, 

and/or the heterocycle mentioned under R3 and R4, formed via a nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 ring heteroatoms from the group consisting of S, N and/or O, optionally also attached via an N function, where the ring systems for their part may be substituted by halogen, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, or 
R3 and R4 together with the nitrogen atom form radicals of the formulae 




 in which 
R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 6 carbon atoms, 
R45 and R45 ′are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, 
R46 represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, 

R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxy or represents straight-chain or branched alkoxy having up to 6 carbon atoms, 
or stereoisomers thereof.

2. A compound selected from the group consisting of:

3. A method for treating a disease or condition mediated by a cGMP-metabolizing phosphodiesterase, wherein said disease or condition is selected from the group consisting of erectile dysfunction, female sexual dysfunction, hypertension, neuronal hypertonia, stable and unstable angina, peripheral and cardial vasculopathies, arrhythmiae, thromboembolic disorders, myocardial infarction, angina pectoris, peripheral circulation obstruction, restenoses after thrombolysis therapy, percutaneous transluminal coronary angioplasties or bypass, stroke, hypertrophy of the prostate and incontinence, comprising administering parentally an effective amount of a compound of formula (I) 




in which
R1 represents straight-chain or branched alkyl having up to 4 carbon atoms, 
R2 represent straight-chain [lacuna] having at least 5 carbon atom or branched alkyl having at least 3 carbon atoms, or represents cycloalkyl having 3 to 10 carbon atoms, 
R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 8 carbon atoms, or represent 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 mono- to trisubstituted by identical or different substituents from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 6 carbon atoms and/or by radicals of the formulae —SO3H, -(A)a-NR7R8, —OC—NR7′R8′, —S(O)b—R9, HN═SO—R9′, —P(O)(OR10)(OR11), 




 in which 
a and b are identical or different and represent a number 0 or 1, 
A represents a radical CO or SO2, 
R7, R7′, R8 and R8′are identical or different and represent hydrogen, or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(SO2)c—NR12R13, 
in which 
c represents a number 0 or 1, 
R12 and R13 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or 

R7, R7′, R8 and R8′ represent straight-chain or branched alkoxy having up to 6 carbon atoms, or 
represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, aryl having from 6 to 10 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(CO)d—NR14R15, 
in which 
R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and 
d represents a number 0or 1, or 

R7 and R8 and/or R7′ and R8′ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR16, 
in which 
R16 represents hydrogen, aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl baying up to 6 carbon atoms, which is optionally substituted by hydroxyl, 

R9 and R9′ are identical or different and represent aryl having 6 to 10 carbon atoms or benzyl, or represent straight-chain or branched alkyl having up to 4 carbon atoms, 
R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, 
and/or the alkyl chain listed above under R3/R4 is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 ring heteroatoms from the group consisting of S, N; O or a radical of the formula —NR17, where the alkyl chain may optionally also be attached via a ring nitrogen atom, 
in which 
R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms, 

and where aryl and the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of nitro, halogen, —SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO2)e—R18R19, 
in which 
e represents a number 0 or 1, 
R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 6 carbon atoms, and/or 

R3 or R4 represent radicals of the formulae —NR20R21 or —(O)-E-NR22R23, 
in which 
R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a 5- or 6-membered saturated heterocycle having a further ring heterocycle from the group consisting of S and O or a radical —NR24, 
in which 
R24 has the meaning of R16 given above and is identical to or different from this meaning, 

E is a straight-chain alkylene group having up to 5 carbon atoms, 
R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning, and/or 

R3 or R4 represent radicals of the formulae 




 or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered partially unsaturated, saturated and unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N; O or a radical of the formula —NR25 which may optionally also be attached via a ring nitrogen atom, 
in which 
R25 has the meaning of R16 given above and is identical to or different from this meaning, or represents carboxyl formyl or straight-chain or branched acyl having up to 5 carbon atoms, 
and where cycloalkyl, aryl and/or the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and/or by groups of the formulae —SO3H, —OR26, (SO2)fNR27R28, —P(O)(OR29 )(OR30), 
in which 
R26 represents a radical of the formula 




 or 
 represents cycloalkyl having 3 to 7 carbon atoms, or hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen, 
f is a number 0 or 1, 
R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula —CO—NH2, 
R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 


and/or cycloalkyl, aryl and/or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or by groups of the formulae —SO2—R31, P(O)(OR32)(OR33) or —NR34R35, 
in which 
R31 is hydrogen or has the meaning of R9 given above and is identical to or different from this meaning, 
R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 
R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or 
R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR36, 
in which 
R36 has the meaning of R16 given above and is identical to or different from this meaning, or 


R1 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N, O or a radical of the formula —NR37, 
in which 
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms, or 
R37 represents a radical of the formula —(CO)g-G, 
in which 
g represents a number 0or 1, 
G represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to unsubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 6 carbon atoms, hydroxyl and trifluoromethyl, 


and the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 6 carbon atoms and groups of the formulae —P(O)(OR38)(OR39) and —(CO)g)—NR40R41, 
in which 
R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning, 
g represents a number 0 or 1, and 
R40 and R41 are identical or different and have the meaning of R18 and R19 given above, 

and/or the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a radical of the formula —SO3H, —NR42R43 or P(O)OR44OR45, 
in which 
R42 and R43 are identical 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, 
R44 and R45 are identical or different and have the meaning of R10 and R11 given above, and/or the alkyl is optionally substituted by benzyloxy or aryl having 6 to 10 carbon atoms, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy or alkylthio having in each case up to 6 carbon atoms, or by a group of the formula —NR42′R43′, 
in which 
R42′ and R43′ have the meaning of R42 and R43 given above and are identical to or different from this meaning, 

and/or the heterocycle mentioned under R3 and R4, formed via a nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 ring heteroatoms from the group consisting of S, N and/or O, optionally also attached via an N function, where the ring systems for their part may be substituted by halogen, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, or 
R3 and R4 together with the nitrogen atom form radicals of the formulae 




 in which 
R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 6 carbon atoms, 
R45 and R45′ are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, 
R46 represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, 

R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxy or represents straight-chain or branched alkoxy having up to 6 carbon atoms, or stereoisomers thereof.

4. The method of claim 3, wherein said compound is administered intra-nasally.

5. The method of claim 3, wherein said cGMP-metabolizing phosphodiesterase is selected from the group consisting of PDE1, PDE2, and PDE5.