2-PHENYL SUBSTITUTED IMIDAZOTRIAZINONES AS PHOSPHODIESTERASE INHIBITORS
The 2-phenyl-substituted imidazotriazinones having short, unbranched alkyl radicals in the 9-position are prepared from the corresponding 2-phenyl-imidazotriazinones by chlorosulphonation and subsequent reaction with the amines. The compounds inhibit cGMP-metabolizing phosphodiesterases and are suitable for use as active compounds in pharmaceuticals, for the treatment of cardiovascular and cerebrovascular disorders and/or disorders of the urogenital system, in particular for the treatment of erectile dysfunction.
1 . 2-Phenyl-substituted imidazotriazinones of the general formula (I)
in which
R 1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R 2 represents straight-chain alkyl having up to 4 carbon atoms,
R 3 and R 4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 8 carbon atoms, or
represents 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- or polysubstituted by identical or different substituents selected from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms and/or by radicals of the formulae —SO 3 H, -(A) a -NR 7 R 8 , —O—CO—NR 7′ R 8′ , —S(O) b —R 9 , —P(O)(OR 10 )(OR 11 ),
in which
a and b are identical or different and each represents a number 0 or 1,
A represents a radical CO or SO 2 ,
R 7 , R 7′ , R 8 and R 8′ are identical or different and each represents hydrogen, or
represents 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 O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(SO 2 ) c —NR 12 R 13 ,
in which
c represents a number 0 or 1,
R 12 and R 13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms,
or
R 7 , R 7′ , R 8 and R 8′ each represent straight-chain or branched alkoxy having up to 6 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, halogen, aryl having 6 to 10 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(CO) d —NR 14 R 15 ,
in which
R 14 and R 15 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and
d represents a number 0 or 1,
or
R 7 and R 8 and/or R 7′ and R 8′ 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 —NR 16 ,
in which
R 16 represents hydrogen, aryl having 6 to 10 carbon atoms, benzyl, a 5- to 7-membered aromatic or saturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O which is optionally substituted by methyl, or
represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl,
R 9 represents aryl having 6 to 10 carbon atoms, or
represents straight-chain or branched alkyl having up to 4 carbon atoms,
R 10 and R 11 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or the alkyl chain listed above under R 3 /R 4 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 heteroatoms from the group consisting of S, N and O or a radical of the formula —NR 17 ,
in which
R 17 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- or polysubstituted by identical or different substituents selected 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- or polysubstituted by identical or different substituents selected from the group consisting of nitro, halogen, —SO 3 H, straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —SO 2 —NR 18 R 19 ,
in which
R 18 and R 19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
and/or
R 3 or R 4 represents a group of the formula —NR 20 R 21 ,
in which
R 20 and R 21 have the meanings of R 18 and R 19 given above and are identical to or different from them,
and/or
R 3 or R 4 represents adamantyl, or represents radicals of the formulae
or represents cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represents a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O, or a radical of the formula —NR 22 ,
in which
R 22 has the meaning of R 16 given above and is identical to or different from it, 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- or polysubstituted by identical or different substituents selected from the group consisting of halogen, triazolyl, 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 —SO 3 H, —OR 23 , (SO 2 ) e NR 24 R 25 , —P(O)(OR 26 )(OR 27 ),
in which
e represents a number 0 or 1,
R 23 represents a radical of the formula
or
represents cycloalkyl having 3 to 7 carbon atoms, or
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, benzyloxy, tetrahydropyranyl, tetrahydrofuranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, carboxyl, benzyloxycarbonyl or phenyl which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen,
and/or alkyl which is optionally substituted by radicals of the formulae —CO—NR 28 R 29 or —CO—R 30 ,
in which
R 28 and R 29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or
R 28 and R 29 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,
and
R 30 represents phenyl or adamantyl,
R 24 and R 25 have the meanings of R 18 and R 19 given above and are identical to or different from them,
R 26 and R 27 have the meanings of R 10 and R 11 given above and are identical to or different from them
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 O, or by groups of the formula —SO 2 —R 31 , P(O)(OR 32 )(OR 33 ) or —NR 34 R 35 ,
in which
R 31 represents hydrogen or has the meaning of R 9 given above and is identical to or different from it,
R 32 and R 33 have the meanings of R 19 and R 11 given above and are identical to or different from them,
R 34 and R 35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms, or
R 34 and R 35 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 —NR 36 ,
in which
R 36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl,
or
R 3 and R 4 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 and O, or a radical of the formula —NR 37 ,
in which
R 37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl 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- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or by groups of the formula -(D) f- NR 38 R 39 , —CO—(CH 2 ) g —O—CO—R 40 , —CO—(CH 2 ) h —OR 41 or —P(O)(OR 42 )(OR 43 ),
in which
g and h are identical or different and each represents a number 1, 2, 3 or 4,
and
f represents a number 0 or 1,
D represents a group of the formula —CO or —SO 2 ,
R 38 and R 39 are identical or different and each has the meaning of R 7 and R 8 given above,
R 40 represents straight-chain or branched alkyl having up to 6 carbon atoms,
R 41 represents straight-chain or branched alkyl having up to 6 carbon atoms,
R 42 and R 43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R 37 represents a radical of the formula —(CO) i -E,
in which
i represents a number 0 or 1,
E represents cycloalkyl having 3 to 7 carbon atoms or benzyl, 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 O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different constituents selected from the group consisting of nitro, halogen, —SO 3 H, straight-chain or branched alkoxy having up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a radical of the formula —SO 2 —NR 44 R 45 ,
in which
R 44 and R 45 have the meaning of R 18 and R 19 given above and are identical to or different from them,
or
E represents radicals of the formulae
and the heterocycle listed under R 3 and R 4 , which is formed together with the nitrogen atom, is optionally mono- or polysubstituted, if appropriate also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and groups of the formulae —P(O)(OR 46 )(OR 47 ),
═NR 48 or —(CO) j NR 49 R 50
in which
R 46 and R 47 have the meanings of R 10 and R 11 given above and are identical to or different from them,
R 48 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
j represents a number 0 or 1,
and
R 49 and R 50 are identical or different and have the meanings of R 14 and R 15 given above,
and/or the heterocycle listed under R 3 and R 4 , which is formed together with the nitrogen atom, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or by a radical of the formula —SO 3 H, —NR 51 R 52 or P(O)OR 53 OR 54 ,
in which
R 51 and R 52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
R 53 and R 54 are identical or different and have the meanings of R 10 and R 11 given above,
and/or the alkyl is optionally substituted by aryl having 6 to 10 carbon atoms which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms, or by a group of the formula —NR 51′ R 52′ ,
in which
R 51′ and R 52′ have the meanings of R 51 and R 52 given above and are identical to or different from them,
and/or the heterocycle listed under R 3 and R 4 , which is formed together with the 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 heteroatoms from the group consisting of S, N and O, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
or
R 3 and R 4 together with the nitrogen atom form radicals of the formulae
R 5 and R 6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or represents straight-chain or branched alkoxy having up to 6 carbon atoms,
and their salts, hydrates, N-oxides and isomeric forms.
2 . 2-Phenyl-substituted imidazotriazinones of the general formula (I) according to claim 1 in which
R 1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R 2 represents straight-chain alkyl having up to 3 carbon atoms,
R 3 and R 4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 6 carbon atoms, or
represents a straight-chain or branched alkyl chain having up to 8 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, and by radicals of the formulae —SO 3 H, -(A) a -NR 7 R 8 , —O—CO—NR 7′ R 8′ , —S(O) b —R 9 , —P(O)(OR 10 )(OR 11 ),
in which
a and b are identical or different and each represents a number 0 or 1,
A represents a radical CO or SO 2 ,
R 7 , R 7′ , R 8 and R 8′ are identical or different and each represents hydrogen, or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula —(SO 2 ) c —NR 12 R 13 ,
in which
c represents a number 0 or 1,
R 12 and R 13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
or
R 7 , R 7′ , R 8 and R 8′ each represent straight-chain or branched alkoxy having up to 3 carbon atoms, or
represents straight-chain or branched alkyl having up to 7 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula —(CO) d —NR 14 R 15 ,
in which
R 14 and R 15 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and
d represents a number 0 or 1,
or
R 7 and R 8 and/or R 7′ and R 8′ together with the nitrogen atom form a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae
in which
R 16 represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or
represents straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl,
R 9 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R 10 and R 11 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and/or the alkyl chain listed under R 3 /R 4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, quinolyl, pyrrolidinyl, pyrimidyl, morpholinyl, furyl, piperidinyl, tetrahydrofuranyl or by radicals of the formulae
in which
R 17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 3 carbon atoms,
or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 4 carbon atoms,
and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, —SO 3 H, straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, hydroxyl, and/or by a radical of the formula —SO 2- NR 18 R 19 ,
in which
R 18 and R 19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or
R 3 or R 4 represents a group of the formula —NR 20 R 21 ,
in which
R 20 and R 21 have the meanings of R 18 and R 19 given above and are identical to or different from them,
and/or
R 3 or R 4 represents adamantyl, or represents radicals of the formulae
or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or represents radicals of the formulae
in which
R 22 has the meaning of R 16 given above and is identical to or different from it, or
represents carboxyl, formyl or straight-chain or branched acyl having up to 3 carbon atoms,
and where cycloalkyl, phenyl and/or the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro and/or by groups of the formulae —SO 3 H, —OR 23 , (SO 2 ) e NR 24 R 25 , —P(O)(OR 26 )(OR 27 ),
in which
e represents a number 0 or 1,
R 23 represents a radical of the formula
or
represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or cycloheptyl,
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which may optionally be substituted by cyclopropyl, cyclopentyl, cyclohexyl, benzyloxy, tetrahydropyranyl, tetrahydrofuranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, benzyloxycarbonyl or phenyl which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl, fluorine and chlorine,
and/or where alkyl is optionally substituted by radicals of the formulae —CO—NR 28 R 29 or —CO—R 30 ,
in which
R 28 and R 29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or
R 28 and R 29 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring,
and
R 30 represents phenyl or adamantyl,
R 24 and R 25 have the meanings of R 18 and R 19 given above and are identical to or different from them,
R 26 and R 27 have the meanings of R 10 and R 11 given above and are identical to or different from them
and/or cycloalkyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula —SO 2 —R 31 , —P(O)(OR 32 )(OR 33 ) or —NR 34 R 35 ,
in which
R 31 has the meaning of R 9 given above and is identical to or different from it,
R 32 and R 33 have the meanings of R 10 and R 11 given above and are identical to or different from them,
R 34 and R 35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
R 34 and R 35 together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring or a radical of the formula
in which
R 36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl,
or
R 3 and R 4 together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of the formula
in which
R 37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
or represents straight-chain or branched alkyl having up to 5 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by groups of the formula -(D) f- NR 38 R 39 , —CO—(CH 2 ) g —O—CO—R 40 , —CO—(CH 2 ) h —OR 41 or —P(O)(OR 42 )(OR 43 ),
in which
g and h are identical or different and each represents a number 1, 2 or 3,
and
f represents a number 0 or 1,
D represents a group of the formula —CO or —SO 2 ,
R 38 and R 39 are identical or different and have the meanings of R 7 and R 8 given above,
R 40 represents straight-chain or branched alkyl having up to 4 carbon atoms,
R 41 represents straight-chain or branched alkyl having up to 4 carbon atoms,
R 42 and R 43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
or
R 37 represents a radical of the formula —(CO) i -E,
in which
represents a number 0 or 1,
E represents cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, where the above-mentioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, —SO 3 H, straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy or by a radical of the formula —SO 2 —NR 44 R 45 ,
in which
R 44 and R 45 have the meanings of R 18 and R 19 given above and are identical to or different from them,
or
E represents radicals of the formulae
and the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro and groups of the formulae —P(O)(OR 46 )(OR 47 ),
═NR 48 or —(CO) j NR 49 R 50
in which
R 46 and R 47 have the meanings of R 10 and R 11 given above and are identical to or different from them,
R 48 represents hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms,
j represents a number 0 or 1,
and
R 49 and R 50 are identical or different and have the meanings of R 14 and R 15 given above,
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 5 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a radical of the formula —SO 3 H, —NR 51 R 52 or —P(O)OR 53 OR 54 ,
in which
R 51 and R 52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R 53 and R 54 are identical or different and have the meanings of R 10 and R 11 given above,
and/or the alkyl is optionally substituted by phenyl which for its part may be mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms, or by a group of the formula —NR 51′ R 52′ ,
in which
R 51′ and R 52′ have the meanings of R 51 and R 52 given above and are identical to or different from them,
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,
or
R 3 and R 4 together with the nitrogen atom form radicals of the formulae
R 5 and R 6 are identical or different and each represents hydrogen, hydroxyl or represents straight-chain or branched alkoxy having up to 4 carbon atoms,
and their salts, hydrates, N-oxides and isomeric forms.
3 . 2-Phenyl-substituted imidazotriazinones of the general formula (I) according to claim 1 in which
R 1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R 2 represents straight-chain alkyl having up to 3 carbon atoms,
R 3 and R 4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 4 carbon atoms, or
represents 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 selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, and/or by radicals of the formulae —SO 3 H, -(A) a -NR 7 R 8 , —O—CO—NR 7′ R 8′ , —S(O) b —R 9 , —P(O)(OR 10 )(OR 11 ),
in which
a and b are identical or different and each represents a number 0 or 1,
A represents a radical CO or SO 2 ,
R 7 , R 7′ , R 8 and R 8′ are identical or different and each represents hydrogen, or
represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula —(SO 2 ) c —NR 12 R 13 ,
in which
c represents a number 0 or 1,
R 12 and R 13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
or
R 7 , R 7′ , R 8 and R 8′ each represent methoxy, or
represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula —(CO) d —NR 14 R 15 ,
in which
R 14 and R 15 are identical or different and each represents hydrogen, methyl or ethyl,
and
d represents a number 0 or 1,
or
R 7 and R 8 and/or R 7′ and R 8′ together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae
in which
R 16 represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or
represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl,
R 9 represents methyl,
R 10 and R 11 are identical or different and each represents hydrogen, methyl or ethyl,
and/or the alkyl chain listed under R 3 /R 4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl, or by radicals of the formulae
in which
R 17 represents hydrogen, hydroxyl, formyl, acetyl or alkoxy having up to 3 carbon atoms,
or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms,
and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, —SO 3 H, straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, hydroxyl, and/or by a radical of the formula —SO 2- NR 18 R 19 ,
in which
R 18 and R 19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and/or
R 3 or R 4 represents a group of the formula —NR 20 R 21 ,
in which
R 20 and R 21 have the meanings of R 18 and R 19 given above and are identical to or different from them,
and/or
R 3 or R 4 represents adamantyl, or represents radicals of the formulae
or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or represents radicals of the formulae
in which
R 22 has the meaning of R 16 given above and is identical to or different from it, or
represents formyl or acetyl,
and where cycloalkyl, phenyl and/or the heterocycles are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, triazolyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, and/or by groups of the formulae —SO 3 H, —OR 23 , (SO 2 ) e NR 24 R 25 , —P(O)(OR 26 )(OR 27 ),
in which
e represents a number 0 or 1,
R 23 represents a radical of the formula
or
represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, benzyloxycarbonyl or phenyl which for its part may be mono- or disubstituted by identical or different substituents selected from the group consisting of methoxy, hydroxyl, fluorine or chlorine,
and/or where alkyl is optionally substituted by radicals of the formulae —CO—NR 28 R 29 or —CO—R 30 ,
in which
R 28 and R 29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R 28 and R 29 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring,
and
R 30 represents phenyl or adamantyl,
R 24 and R 25 have the meaning of R 18 and R 19 given above and are identical to or different from them,
R 26 and R 27 have the meanings of R 10 and R 11 given above and are identical to or different from them
and/or cycloalkyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula —SO 2 —R 31 , P(O)(OR 32 )(OR 33 ) or —NR 34 R 35 ,
in which
R 31 represents methyl,
R 32 and R 33 have the meanings of R 10 and R 11 given above and are identical to or different from them,
R 34 and R 35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl or methoxy, or
R 34 and R 35 together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring or a radical of the formula
in which
R 36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl,
or
R 3 and R 4 together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of the formula
in which
R 37 represents hydrogen, hydroxyl, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formula -(D) f- NR 38 R 39 , —CO—(CH 2 ) g —O—CO—R 40 , —CO—(CH 2 ) h —OR 41 or —P(O)(OR 42 )(OR 43 ),
in which
g and h are identical or different and each represents a number 1 or 2,
and
f represents a number 0 or 1,
D represents a group of the formula —CO or —SO 2 ,
R 38 and R 39 are identical or different and have the meanings of
R 7 and R 8 given above,
R 40 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R 41 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R 42 and R 43 are identical or different and each represents hydrogen, methyl or ethyl,
or
R 37 represents a radical of the formula —(CO) i -E,
in which
represents a number 0 or 1,
E represents cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, —SO 3 H, straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl, or by a radical of the formula —SO 2 —NR 44 R 45 ,
in which
R 44 and R 45 have the meanings of R 18 and R 19 given above and are identical to or different from them,
or
E represents radicals of the formulae
and the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or groups of the formulae —P(O)(OR 46 )(OR 47 ),
═NR 48 or —(CO) j NR 49 R 50
in which
R 46 and R 47 have the meanings of R 10 and R 11 given above and are identical to or different from them,
R 48 represents hydroxyl or methoxy,
j represents a number 0 or 1,
and
R 49 and R 50 are identical or different and have the meanings of R 14 and R 15 given above,
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, 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 selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a radical of the formula —SO 3 H, —NR 51 R 52 or P(O)OR 53 OR 54 ,
in which
R 51 and R 52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
R 53 and R 54 are identical or different and have the meanings of R 10 and R 11 given above,
and/or the alkyl is optionally substituted by phenyl which for its part may be mono- to disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, hydroxyl, methoxy, or by a group of the formula —NR 51′ R 52′ ,
in which
R 51′ and R 52′ have the meanings of R 51 and R 52 given above and are identical to or different from them,
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, if appropriate also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
or
R 3 and R 4 together with the nitrogen atom form radicals of the formulae
R 5 and R 6 are identical or different and each represents hydrogen, hydroxyl or represents straight-chain or branched alkoxy having up to 3 carbon atoms,
and their salts, hydrates, N-oxides and isomeric forms.
4 . 2-Phenyl-substituted imidazotriazinones of the general formula (I) according to claim 1 in which
R 1 represents methyl or ethyl,
R 2 represents ethyl or propyl,
R 3 and R 4 are identical or different and each represents a straight-chain or branched alkyl chain having up to 5 carbon atoms which is optionally substituted up to two times by identical or different substituents selected from the group consisting of hydroxyl and methoxy,
or
R 3 and R 4 together with the nitrogen atom form a piperidinyl, morpholinyl, thiomorpholinyl ring, or a radical of the formula
in which
R 37 represents hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formulae -(D) f- NR 38 R 39 or —P(O)(OR 42 )(OR 43 ),
in which
f represents a number 0 or 1,
D represents a group of the formula —CO,
R 38 and R 39 are identical or different and each represents hydrogen or methyl,
R 42 and R 43 are identical or different and each represents hydrogen, methyl or ethyl,
or
R 37 represents cyclopentyl,
and the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally mono- or disubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or groups of the formulae —P(O)(OR 46 )(OR 47 ) or —(CO) i NR 49 R 50 ,
in which
R 46 and R 47 are identical or different and each represents hydrogen, methyl or ethyl,
j represents a number 0 or 1,
and
R 49 and R 50 are identical or different and each represents hydrogen or methyl
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, or by a radical of the formula P(O)OR 53 OR 54 ,
in which
R 53 and R 54 are identical or different and each represents hydrogen, methyl or ethyl,
and/or the heterocycles listed under R 3 and R 4 , which are formed together with the nitrogen atom, are optionally substituted by pyrrolidinyl or piperidinyl attached via nitrogen,
R 5 represents hydrogen,
and
R 6 represents ethoxy or propoxy,
and their salts, hydrates, N-oxides and isomeric forms.
5 . 2-Phenyl-substituted imidazotriazinones according to claims 1 to 4 having the following structures:
Structure
6 . 2-Phenyl-substituted imidazotriazinones of the general formula (I) according to claim 1 for the treatment of disorders.
7 . Process for preparing 2-phenyl-substituted imidazotriazinones according to claim 1 , characterized in that
initially compounds of the general formula (II)
in which
R 1 and R 2 are each 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
R 5 and R 6 are each as defined above,
in a two-step reaction in the systems ethanol and phosphorus oxytrichloride/dichloroethane into the compounds of the general formula (IV)
in which
R 1 , R 2 , R 5 and R 6 are each as defined above,
which are reacted in a further step with chlorosulphonic acid to give the compounds of the general formula (V)
in which
R 1 , R 2 , R 5 and R 6 are each as defined above,
which are finally reacted with amines of the general formula (VI)
HN 3 R 4 (VI)
in which
R 3 and R 4 are each as defined above,
in inert solvents.
8 . Pharmaceuticals which comprise at least one 2-phenyl-substituted imidazotriazinone according to claim 1 and pharmacologically acceptable formulating agents.
9 . Pharmaceuticals according to claim 8 for the treatment of cardiovascular, cerebrovascular disorders and/or disorders of the urogenital tract.
10 . Pharmaceuticals according to claim 9 for the treatment of erectile dysfunction.
11 . The use of 2-phenyl-substituted imidazotriazinones according to claim 1 for preparing pharmaceuticals.