Details for Patent: 7,314,871

Title:	2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors, for treatment of hypertension
Abstract:	The application claims a method for treating hypertension by administering an effective amount of a compound of the formula (I) ##STR00001## wherein the variable groups are as defined in the specification and claims. These 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.
Inventor(s):	Niewohner, legal representative; Maria (Wermelskirchen, DE), Es-Sayed; Mazen (Langenfeld, DE), Haning; Helmut (Wuppertal, DE), Schenke; Thomas (Bergisch Gladbach, DE), Schlemmer; Karl-Heinz (Wuppertal, DE), Keldenich; Jorg (Wuppertal, DE), Bischoff; Erwin (Wuppertal, DE), Perzborn; Elisabeth (Wuppertal, DE), Dembowsky; Klaus (Boston, MA), Serno; Peter (Bergisch Gladbach, DE), Nowakowski; Marc (Wuppertal, DE), Niewohner, deceased; Ulrich (Wermelskirchen, DE)
Assignee:	Bayer Aktiengesellschaft (Leverkusen, DE)
Filing Date:	Apr 21, 2006
Application Number:	11/409,417
Claims:	1. A method for the treatment of hypertension comprising intranasally administering to a mammal an effective amount of a compound of the formula (I) ##STR00413## in which R.sup.1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R.sup.2 represents straight-chain alkyl having up to 4 carbon atoms, R.sup.3 and R.sup.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.sub.3H, -(A).sub.a-NR.sup.7R.sup.8, --O--CO--NR.sup.7'R.sup.8', --S (O).sub.b--R.sup.9, --P(O)(OR.sup.10)(OR.sup.11), ##STR00414## in which a and b are identical or different and each represents a number 0 or 1, A represents a radical CO or SO.sub.2, R.sup.7, R.sup.7', R.sup.8 and R.sup.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.sub.2).sub.c--NR.sup.12R.sup.13, in which c represents a number 0 or 1, R.sup.12 and R.sup.13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or R.sup.7, R.sup.7', R.sup.8 and R.sup.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).sub.d--NR.sup.14R.sup.15, in which R.sup.14 and R.sup.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.sup.7 and R.sup.8 and/or R.sup.7' and R.sup.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.sup.16, in which R.sup.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.sup.9 represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, R.sup.10 and R.sup.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.sup.3/R.sup.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.sup.17, in which R.sup.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.sub.3H, 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.sub.2--NR.sup.18R.sup.19, in which R.sup.18 and R.sup.19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and/or R.sup.3 or R.sup.4 represents a group of the formula --NR.sup.20R.sup.21, in which R.sup.20 and R.sup.21 have the meanings of R.sup.18 and R.sup.19 given above and are identical to or different from them, and/or R.sup.3 or R.sup.4 represents adamantyl, or represents radicals of the formulae ##STR00415## 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.sup.22, in which R.sup.22 has the meaning of R.sup.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.sub.3H, --OR.sup.23, (SO.sub.2).sub.eNR.sup.24R.sup.25, --P(O)(OR.sup.26)(OR.sup.27), in which e represents a number 0 or 1, R.sup.23 represents a radical of the formula ##STR00416## 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.sup.28 R.sup.29 or --CO--R.sup.30, in which R.sup.28 and R.sup.29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or R.sup.28 and R.sup.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.sup.30 represents phenyl or adamantyl, R.sup.24 and R.sup.25 have the meanings of R.sup.18 and R.sup.19 given above and are identical to or different from them, R.sup.26 and R.sup.27 have the meanings of R.sup.10 and R.sup.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.sub.2--R.sup.31, P(O)(OR.sup.32)(OR.sup.33) or --NR.sup.34R.sup.35, in which R.sup.31 represents hydrogen or has the meaning of R.sup.9 given above and is identical to or different from it, R.sup.32 and R.sup.33 have the meanings of R.sup.10 and R.sup.11 given above and are identical to or different from them, R.sup.34 and R.sup.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.sup.34 and R.sup.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.sup.36, in which R.sup.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.sup.3 and R.sup.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.sup.37, in which R.sup.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).sub.fNR.sup.38R.sup.39, --CO--(CH.sub.2).sub.g--O--CO--R.sup.40, --CO--(CH.sub.2).sub.h--OR.sup.41 or --P(O) (OR.sup.42)(OR.sup.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.sub.2, R.sup.38 and R.sup.39 are identical or different and each has the meaning of R.sup.7 and R.sup.8 given above, R.sup.40 represents straight-chain or branched alkyl having up to 6 carbon atoms, R.sup.41 represents straight-chain or branched alkyl having up to 6 carbon atoms, R.sup.42 and R.sup.43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or R.sup.37 represents a radical of the formula -(CO).sub.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.sub.3H, straight-chain or branched alkoxy having up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a radical of the formula --SO.sub.2--NR.sup.44R.sup.45, in which R.sup.44 and R.sup.45 have the meaning of R.sup.18 and R.sup.19 given above and are identical to or different from them, or E represents radicals of the formulae ##STR00417## and the heterocycle listed under R.sup.3 and R.sup.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.sup.46)(OR.sup.47), ##STR00418## in which R.sup.46 and R.sup.47 have the meanings of R.sup.10 and R.sup.11 given above and are identical to or different from them, R.sup.48 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, J represents a number 0 or 1, and R.sup.49 and R.sup.50 are identical or different and have the meanings of R.sup.14 and R.sup.15 given above, and/or the heterocycle listed under R.sup.3 and R.sup.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 substituents selected 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 or alkoxycarbonyl having in each case up to 6 carbon atoms, or by a radical of the formula --SO.sub.3H, --NR.sup.51R.sup.52 or P(O)OR.sup.53OR.sup.54, in which R.sup.51 and R.sup.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.sup.53 and R.sup.54 are identical or different and have the meanings of R.sup.10 and R.sup.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.sup.51'R.sup.52', in which R.sup.51' and R.sup.52' have the meanings of R.sup.51 and R52 given above and are identical to or different from them, and/or the heterocycle listed under R.sup.3 and R.sup.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.sup.3 and R.sup.4 together with the nitrogen atom form radicals of the formulae ##STR00419## R.sup.5 and R.sup.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, or a salt, hydrate, hydrate of a salt, N-oxide, or isomeric form thereof. 2. The method of claim 1, wherein the compound of formula (I) is ##STR00420## or a salt, hydrate, or hydrate of a salt thereof.