HK1017680A - Sulfonamide-substituted compounds, processes for their prepartion, their use as a medicament oder diagnostic, and medicament comprising them - Google Patents

Description

Sulfonamide-substituted compounds, process for their preparation, their use and medicaments containing them

The invention relates to compounds of formula (I), to a method for the production thereof and to the use thereof, in particular as medicamentsWherein R (1), R (2), R (3), R (4), R (5), R (6), R (7) and R (8) have the meanings given below.

Potassium channels opened by cyclic adenosine monophosphate (cAMP) or I_ksThe channels exert an influence and are outstandingly suitable as pharmaceutically active compounds, for example for the prophylaxis and treatment of cardiovascular diseases, in particular arrhythmias, for the treatment of gastrointestinal ulcers or for the treatment of diarrhoea.

The medicinal chemistry of 4-acylaminochroman derivatives has been intensively studied in recent years. The most representative of this class is cromakalim of formula A (J. chem. Soc. Perlin trans.1,1991,63-70)cromaALim and other related 4-acylaminochroman derivatives are compounds having a relaxing effect on smooth muscle organs, and thus they are useful for lowering elevated blood pressure by relaxing vascular muscles and for treating asthma by relaxing the smooth muscle system of the respiratory tract. These agents usually act at the cellular level, for example, on smooth muscle cells and thereby open specific ATP-sensitive K⁺A channel. From K⁺The increase of negative charge in cells caused by ion efflux (hyperpolarization) counteracts intracellular Ca by a second mechanism⁺The concentration is increased, thereby activating the cells, thereby causing, for example, muscle contraction.

The literature discloses so-called pyranopyridines (formula B) which are structurally analogous to the compounds of formula I. However, we focus here on 4-acylamino derivatives, which likewise have K-ATP channel blocking properties.

The compounds of formula I of the present invention differ in structure from these amido derivatives, in particular the amido group is replaced by a sulfonamido group. Although Cromakalim (formula A) and similar amido compounds are used as ATP-sensitive K⁺Channel openers, but the compounds of the formula I according to the invention having a sulfonamido structure do not have any opening K⁺(ATP) channel, but surprisingly cyclic adenosine monophosphate (cAMP) opening and with the above mentioned K⁺(ATP) radically different channels K⁺The channel shows a strong, specific blocking (closing) effect. Recent studies have shown that K is present in colon tissue⁺(cAMP) channels are very small, or even with I in the myocardium_KsThe channels are identical. In fact, the compounds of formula I of the present invention may be used for treating myocardial cell I of guinea pig_KsPassage and I in Xenopus oocytes_sKThe channels showed strong blocking. Due to this pair K⁺(cAMP) channel or I_KsThe channel blocking effect, the compound of the present invention shows a pharmaceutical effect with high therapeutic value in vivo.

The invention relates to compounds of formula (I) and to their physiologically tolerated saltsWherein R (1) and R (2) are independently of each other hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms, which are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; or R (1) and R (2) together are an alkylene chain having 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms; in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r (3) is R (12) -C_aH_2a[NR(13)]_m-; r (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇(ii) a a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms; or R (12) and R (13) together are an alkylene group having 4, 5, 6, 7 or 8 carbon atoms, wherein one CH on the alkylene chain₂The radicals may be substituted by-O-, - [ SO ]_{0.1 or 2}]-, -CO-or-NR (10) -; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r (4) is R (14) -C_rH_2r(ii) a r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl, which are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino; wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-, or-NR (11) -substitution; r (11) is hydrogen or- (C)_aH_2a) -R (10); wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) substitution; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R (3) and R (4) together are an alkylene group having 3,4, 5, 6, 7 or 8 carbon atoms, wherein one CH on the alkylene chain₂The radicals may be substituted by-O-, - [ SO ]_{0.1 or 2}]-, -CO-or-NR (11) -; r (11) is hydrogen or- (C)_aH_2a) -R (10) wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution; r (10) is hydrogenOr an alkyl group having 1, 2 or 3 carbon atoms; r (5) and R (6) are-CR (15) = CR (16) -CR (17) = N-, -CR (15) = CR (16) -N = CR (17) -, -CR (15) = N-CR (17) = N-, -CR (15) = N-N = CR (17) -, -N = CR (16) -CR (17) = N-, or-S-CR (15) = CR (16) -; r (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR (19) R (20); wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; u is 2 or 3; r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; s is 0, 1, 2, 3,4, 5 or 6; z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO_{(0, 1 or 2)}-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-; r (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3 or 4 carbon atoms, acyloxy having 1, 2, 3 or 4 carbon atoms, Cl, Br, F, alkyl having 1, 2, 3 or 4 carbon atoms; r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

Preferred compounds of formula i are the following compounds and their physiologically tolerated salts, wherein: r (1) and R (2) are each otherIndependently of each other is hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms, which are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms; in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r (3) is R (12) -C_aH_2a[NR(13)]_m-; r (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇(ii) a a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms; r (4) is R (14) -C_rH_2r(ii) a r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl, which are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino; wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution; r (11) is hydrogen or- (C)_aH_2a) -R (10); wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution; a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; r (5) and R (6) are-CR (15) = CR (16) -CR (17) = N-, -CR (15) = CR (16) -N = CR (17) -, -CR (15) = N-CR (17) = N-, -CR (15) = N-N = CR (17) -, -N= CR (16) = CR (17) = N-or-S-CR (15) = CR (16) -; r (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR (19) R (20); u is 2 or 3; r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl; r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; s is 0, 1, 2, 3,4, 5 or 6; z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-; r (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3 or 4 carbon atoms, acyloxy having 1, 2, 3 or 4 carbon atoms, Cl, Br, F, alkyl having 1, 2, 3 or 4 carbon atoms; r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

Particularly preferred compounds of the formula i are the following compounds and their physiologically tolerated salts, in which: r (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms,they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms; in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r (3) is R (12) -C_aH_2a[NR(13)]_m-; r (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇(ii) a a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms; r (4) is R (14) -C_rH_2r(ii) a r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl, which are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino; wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution; r (11) is hydrogen or- (C)_aH_2a) -R (10); wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution; r (5) and R (6) are-CR (15) = CR (16) -CR (17) = N-or-CR (15) = CR (16) -N = CR (17) -; r (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR (19) R (20); u is 2 or 3; r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl; r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl; s is 0, 1, 2, 3,4, 5 or 6; z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-; r (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3, or 4 carbon atoms, alkyl having 1, 2, 3, or 4 carbon atoms; r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

The most preferred compounds of formula i are the following compounds and their physiologically tolerated salts, wherein: r (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms, which are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; or R (1) and R (2) together are an alkylene chain having 2, 3,4, 5 or 6 carbon atoms; in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -Replacement; r (10) is hydrogen or an alkyl chain having 1, 2 or 3 carbon atoms; r (3) is R (12) -C_aH_2a-; r (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇(ii) a a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; r (4) is R (14) -C_rH_2r(ii) a r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl, which are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino; wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution; r (11) is hydrogen or- (C)_aH_2a) -R (10); wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution; r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r (5) and R (6) are

-CR (15) = CR (16) -CR (17) = N-or

-CR (15) = CR (16) -N = CR (17) -; r (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl; r (19) is hydrogen or an alkane having 1, 2, or 3 carbon atomsA group; r (21) is hydrogen, methyl, ethyl or phenyl, wherein the phenyl is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl; r (22) is hydrogen; s is 0, 1, 2, 3,4, 5 or 6; z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-; r (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3, or 4 carbon atoms, alkyl having 1, 2, 3, or 4 carbon atoms; r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

If the compounds I contain acidic or basic groups or basic heterocycles, the invention also relates to the corresponding pharmacologically or toxicologically tolerable salts. Thus, compounds I which carry one or more COOH groups can be used in the form of alkali metal salts, for example sodium or potassium salts. The compounds I which bear basic, protonatable or basic heterocyclic groups can also be used in the form of their organic or inorganic pharmacologically and toxicologically tolerable acid addition salts, such as, for example, the hydrochloride, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate and the like. If the compounds I contain acidic and basic groups in the same molecule, then, in addition to the salts mentioned above, the invention also includes internal salts, the so-called betaines.

If appropriately substituted, the compounds of the formula I may exist in stereoisomeric form. If the compounds of the formula I contain one or more asymmetric centers, they can, independently of one another, have the S configuration or the R configuration. The present invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, such as enantiomers and/or diastereomers, in any desired ratio. The invention therefore relates to enantiomers such as pure enantiomers, including the levorotatory and dextrorotatory enantiomers, and also to the mixed or racemic forms of the two enantiomers in different proportions. If cis/trans isomers are present, the present invention relates to both the cis and trans forms and mixtures thereof. If desired, individual stereoisomers may be prepared by resolution of a mixture using conventional methods, or by stereospecific synthesis, for example. If a mobile hydrogen atom is present, the invention also includes all tautomeric forms of the compounds of formula I.

The alkyl and alkylene groups may be straight or branched.

The compounds of formula I can be prepared using different chemical processes, and the invention also relates to these chemical processes.

The compounds of the formula I are thus obtained by a) the compounds of the formula II are reacted in a manner known per seWherein R (1), R (2), R (5), R (6), R (7) and R (8) have the above-mentioned meanings and L is a conventional nucleofugic leaving group, in particular F, Cl, Br, I, MeSO₂-O-, p-toluenesulfonyloxy, or R (7) and L together are an epoxide ring, with a sulfonamide of formula IIId or a salt thereofWherein R (3) and R (4) have the above-mentioned meanings, M is hydrogen or a preferably equivalent metal, preferably lithium, sodium or potassium; or b) reacting a compound of the formula IVWherein R (1), R (2), R (4), R (5), R (6), R (7) and R (8) have the abovementioned meanings, with sulfonic acid derivatives of the formula VWherein R (3) has the above-mentioned meaning and W is a nucleofugic leaving group, such as fluorine, bromine, 1-imidazolyl, but preferably chlorine; or c) reacting the compound of the formula VI under alkylation conditions in a manner known per seWherein R (1), R (2), R (3), R (5), R (6), R (7), R (8) and M have the above-mentioned meanings, with an alkylating agent of the formula VII R (4) -L VII, wherein R (4) is not hydrogen and L has the above-mentioned meaning; or d) if at least one of the R (15), R (16), R (17) positions on the ring system R (5) -R (6) is hydrogen and the other substituents R (1) to R (8) have the abovementioned meaning, areNucleophilic substitution of at least one of the R (15), R (16), R (17) positions of the ring system R (5) -R (6) of the compounds of the formula IWherein R (1) to R (4), R (7) and R (8) have the above-mentioned meanings. Method a)

The reaction of a sulphonamide of formula III or one of its salts with a reactive heterocycle of formula II is described. The reaction carried out using the sulfonamide of formula iii in the form of a salt, unlike the use of the free sulfonamide (formula iii, M = H), the sulfonamide salt has a higher nucleophilicity and therefore must be rendered more active by the action of a base. If free sulfonamides (M = H) are used, the sulfonamides are preferably deprotonated in situ to form salts using bases which are not themselves alkylated or are only slightly alkylated, for example sodium carbonate, potassium carbonate, strongly sterically hindered amines (e.g.dicyclohexylamine, N, N, N-dicyclohexylethylamine) or other strongly nitrogen bases of low nucleophilicity (e.g.DBU, N, N' -triisopropylguanidine, etc.). It is of course also possible to use other bases which are customarily used for the reaction, for example potassium tert-butoxide, sodium methoxide, alkyl metal hydrogen carbonates, alkali metal hydroxides (for example LiOH, NaOH or KOH) or alkaline earth metal hydroxides (for example Ca (OH))₂)。

The reaction is preferably carried out in a polar organic solvent such as dimethylformamide, dimethylacetamide, tetramethylurea, hexamethylphosphoramide, tetrahydrofuran, dimethoxyethane, toluene, a halogenated hydrocarbon (e.g., chloroform or dichloromethane), and the like. Of course, the reaction can also be carried out in polar protic solvents, such as water, methanol, ethanol, isopropanol, ethylene glycol or its oligomers and their corresponding half-ethers and ethers. The reaction is preferably carried out at a temperature of from-10 ℃ to 140 ℃, particularly preferably from 20 ℃ to 100 ℃. It is also preferred that process a) is carried out under two-phase catalytic conditions.

The compounds of the formula II can be obtained by methods known in the literature, for example by inorganic or organic peroxides (e.g. H)₂O₂MCPBA, peracetic acid) from the corresponding unsaturated compound Xhalogen/OH can also be introduced by reaction of X with NCS, NBS, chlorine or bromine in an aqueous solvent. Epoxides can be prepared from hydrogen halides by elimination of the H-halogen with various bases (R (7) and L form an epoxide ring). Preferably, the reaction is carried out in a solvent sufficiently inert to the halogenating or oxidizing agents, for example in DMSO or a halogenated hydrocarbon (e.g., chloroform, dichloromethane). Method b)

The reaction of an activated sulfonyl compound of the formula v, in particular a chlorosulfonyl compound (W = Cl), with an amino derivative of the formula iv to give the corresponding sulfonamide derivative of the formula i is described, known per se and frequently used. In theory, the reaction can be carried out without solvent, but such reactions are usually carried out in a solvent.

The reaction is preferably carried out using protic solvents, preferably in the presence of bases which can themselves be used as solvents, for example triethylamine, in particular pyridine and its homologues. Solvents which are likewise suitable are, for example, water, aliphatic alcohols (e.g. methanol, ethanol, isopropanol, sec-butanol, ethylene glycol) and monomeric and oligomeric monoalkyl and dialkyl ethers thereof, tetrahydrofuran, dioxane, dialkylated amides (e.g. DMF, DMA) and TMU and HMPT. The reaction is carried out at a temperature of 0 to 160 ℃ and preferably 20 to 100 ℃.

The amino derivatives of the formula IV are obtained by methods known in the literature, preferably by reacting an active compound of the formula II, in which R (1), R (2), R (5), R (6) and L are as defined above, with ammonium or an amine of the formula XI, R (4) -NH XI, in which R (4) is as defined above. Method c)

The alkylation of a sulphonamide of the formula VI or one of its salts with an alkylating agent of the formula VII is described, which is known per se. The reaction conditions specified in process a) apply to process c) using reactions analogous to process a).

The preparation of the sulfonamide derivatives VI and their precursors is described in process b). The preparation of the alkylating reagent VII is carried out analogously to what is described in the literature or in method a), preferably from the corresponding hydroxy compound (of the formula VII in which L is-OH). Method d)

Further chemical conversion of the compounds of formula I of the present invention to other compounds of formula I by electrophilic substitution at one or more positions defined by R (5) to R (8), which positions are hydrogen, is described.

A preferred substitution reaction is 1. aromatic nitration, introduction of one or more nitro groups, followed by reduction to NH₂Aromatic halogenation, in particular introduction of chlorine, bromine or iodine, 3 chlorosulfonylation by action of chlorosulfonic acid, introduction of chlorosulfonyl groups, 4 Friedel-Crafts acylation, introduction of acyl groups according to methods known from the literature.

In all methods, functional groups in the molecule may be temporarily protected in certain reaction steps. Such protecting group techniques are well known to those skilled in the art. The choice of the protecting groups and their introduction and removal processes have been described in the literature and, if appropriate and without difficulty, they are suitable in a variety of situations.

As already mentioned, the compounds of the formula I on K⁺The channels have an unexpectedly strong, specific blocking (closing) effect, the K⁺The channel is opened by cyclic adenosine monophosphate (cAMP) and is fundamentally different from the well-known K⁺(ATP) channel, K in colonic tissue⁺(cAMP) channels are very small, or even with I in the myocardium_KsThe channels are identical. The compound of formula I of the invention can be used for treating I in guinea pig myocardial cells_KsPassage and I in Xenopus oocytes_sKThe channels showed strong blocking. Due to this pair K⁺(cAMP) channel or I_KsThe channel blocking effect, the compounds of the present invention exhibit pharmaceutical effects with high therapeutic value in vivo and are particularly useful as pharmaceutically active compounds for the treatment and prevention of various symptoms.

The compounds of formula i according to the invention are therefore a novel class of active compounds which are effective inhibitors of the stimulation of gastric acid secretion. The compounds of formula i are therefore effective pharmaceutically active compounds for the treatment and prophylaxis of gastric and intestinal ulcers (e.g. duodenal ulcers). Due to their strong gastric secretion-inhibiting action, they are also suitable as therapeutic agents for the treatment and prevention of digestive esophagitis.

The compounds of the formula I according to the invention also have antidiarrheal action and are therefore suitable as pharmaceutically active compounds for the treatment and prophylaxis of diarrheal diseases.

The compounds of the formula I according to the invention are also suitable as pharmaceutically active compounds for the treatment and prophylaxis of cardiovascular diseases. In particular, they are useful for the treatment and prevention of all types of arrhythmia, including atrial, ventricular and supraventricular arrhythmias, and in particular arrhythmias that can be eliminated by a potentially prolonged action. They are particularly useful for the treatment and prevention of atrial fibrillation and atrial flutter, and for the treatment and prevention of reentry arrhythmias, and for the prevention of sudden cardiac death due to ventricular fibrillation.

Although there are many substances having antiarrhythmic activity on the market, none of the compounds is actually satisfactory in terms of activity, range of application and side effects, and therefore development and improvement of antiarrhythmic drugs are still required.

The action of various known antiarrhythmic drugs of the so-called class III is based on an increase in the refractory period of the myocardium by prolonging the potential duration of action. This can be done via various Ks⁺Repolarization of channel-efflux cells⁺The extent of flow. Of particular importance is the so-called "delayed rectifier" I in this context_KIn which two subtypes, rapidly activated I_KrAnd slow activated I_Ks. Most known class III antiarrhythmic drugs (e.g., dofetilide and d-sotalol) predominantly or exclusively block I_Kr. However, these compounds are shown to have a risk of pre-elevation arrhythmias for either bradycardia or normal heart rates. In particular, arrhythmia known as "Torsades de pointes" was observed (D.M. roden; "Current State of class III antiarrhythmic drug therapy"; American journal of Heart science, 72(1993), 44B-49B). But at a higher heart rate orIn the case of stimulated beta-receptors, I_krThe potential prolonged action of the retarder is significantly reduced due to I under these conditions_KsMaking the repolarization stronger. For these reasons, the present invention is used as I_KsSubstances of retarding agents with the known compounds I_krRetarders have significant advantages over others. At the same time, there is also relation to I_KsA certain relationship between channel inhibition and life-threatening arrhythmias is described, for example, by β -adrenergic hyperstimulation (e.g., T.J.Colatsky, C.H, Follmer and C.F.Starmer; "channel specificity in antiarrhythmic drugs;" mechanism of potassium channel blockade and its effect in inhibiting and exacerbating arrhythmias "; cycle 82(1990), 2235;" A.E.Busch, K.Malloy, W.J.Groh, M.D.Varnum, J.P.Adelman and J.Maylie; "New class III antiarrhythmics NE-10064 and NE-10133 inhibit I in Xenopus oocytes_sKI in channels and guinea pig cardiomyocytes_KsA channel "; biochemical and biophysical research communications, 202(1994),265- & 270).

Furthermore, the compounds of the invention significantly ameliorate cardiac insufficiency, in particular congestive heart failure, and preferably they are used in combination with active compounds that promote contraction (enhance contractility), such as phosphodiesterase inhibitors.

Although by retardation I_KsTherapeutically utilizable advantages can be obtained, and only very small amounts of several compounds inhibiting this "delayed rectifier" subtype have been described to date. Undeniably, azimilide under development is also on I_KsHas a retarding action, but its main retardation I_kr(selectivity 1: 10). WO-A-95/14470 claims benzodiazepines  as Selectivity I_KsUse of a blocking agent. In FEBS Letters 396(1996), 271-: "specific blocking of Slow activation by chromanol I_sKChannel … "and the methods described in Pfugers arch. -eur.j.physiol.429(1995), 517-530: "A novel class of cAMP-mediated Cl in the colon of rabbits^-Secretion inhibitors by decreasing cAMP-activated K⁺Conducting action "other I are described_KsA retarder. But wherein the water solubility of the compound is low.

The compounds of the formula I according to the invention and their physiologically tolerated salts can therefore be used as medicaments per se, in mixtures with one another or in pharmaceutical preparations for animal, preferably mammalian, in particular human, animals. The invention also relates to compounds of formula (I) and their physiologically tolerated salts which are suitable as medicaments, to their use for the treatment and prophylaxis of the abovementioned conditions and to their use for producing medicaments for the abovementioned use and medicaments having K⁺The application of the channel blocking medicine. Furthermore, the invention relates to pharmaceutical preparations containing an effective dose of at least one compound of the formula i and/or physiologically tolerated salts thereof as active ingredient, which is added to customary pharmaceutically harmless excipients and auxiliaries. The pharmaceutical preparations usually contain 0.1 to 90% by weight of the compounds of the formula I and/or their physiologically tolerated salts. The pharmaceutical preparations can be prepared according to methods known per se. For this purpose, the compounds of the formula I and/or their physiologically tolerated salts are brought into a form or dosage form suitable for administration in human or veterinary medicine, in combination with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, with other pharmaceutically active compounds.

The medicaments containing the compounds of the formula I and/or their physiologically tolerated salts according to the invention can be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, preferably as the case may be, for example according to the course of the disease to be treated.

The person skilled in the art is familiar with the auxiliaries suitable for the desired pharmaceutical preparations on the basis of his expert knowledge. In addition to solvents, gelling agents, suppository bases, tablet auxiliaries and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, auxiliary solvents, agents for achieving a depot effect, buffer substances or colorants.

The compounds of formula I may also be combined with other pharmaceutically active compounds to achieve advantageous therapeutic effects. Therefore, in the treatment of cardiovascular diseases, it may be preferable to combine it with a substance having cardiovascular activityAnd (4) combining. Such ingredients which can be used in combination and which are advantageous for the treatment of cardiovascular diseases are, for example, other antiarrhythmic agents, i.e.class I, II or III antiarrhythmic agents, e.g.I_KrChannel blockers, such as dofetilide, or also hypotensive substances such as ACE inhibitors (e.g. enalapril, captopril, ramipril), angiotensin antagonists, K⁺Channel activators and alpha-and beta-receptor blockers, as well as sympathomimetic and adrenergic compounds, and also Na⁺/H⁺Exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances with inotropic activity (e.g. digitonin) or diuretics. It is also advantageous to combine substances having antibiotic activity with antiulcer agents, for example with H₂Antagonists (e.g., ranitidine, cimetidine, famotidine, etc.) bind, especially when used in the treatment of gastrointestinal disorders.

For oral dosage forms, the active compound is mixed with additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and brought into a form suitable for administration by customary methods, for example tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert excipients which may be used are, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch (in particular corn starch). In this case, the preparation can be carried out using dry or wet granules. Suitable oil excipients or solvents are, for example, vegetable oils or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Other adjuvants suitable for other forms of administration are, for example, polyethylene glycol and polypropylene glycol.

For subcutaneous or intravenous administration, the active compounds, if desired together with substances customary therefor, such as stabilizers, emulsifiers or other auxiliaries, are brought into solution, suspension or emulsion. The compounds of formula I and their physiologically tolerated salts can also be lyophilized and the resulting lyophilizates used for the preparation of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solutions or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions, for example glucose or mannose solutions, or mixtures of the above-mentioned solvents are used.

Pharmaceutical preparations which are suitable for administration in the form of an aerosol or spray are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerated salts in pharmaceutically acceptable solvents, such as, in particular, ethanol or water, or mixtures of these solvents. The formulations may also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, and propellants, if desired. The preparations generally contain the active compound in a concentration of about 0.1 to 10% by weight, in particular 0.3 to 3% by weight.

The active compounds of formula i or their physiologically tolerated salts are administered in dosages which depend on the particular circumstances and are generally adapted to the circumstances of the particular patient and to achieve optimum results. The dosage administered thus depends on the number of administrations and on the potency and duration of action of the therapeutic or prophylactic compound, as well as on the nature and severity of the disease to be treated, and on the sex, age, weight and specific response of the human or animal to be treated, and on whether the treatment is acute or prophylactic. In general, the daily dose of a compound of formula I administered is at least 0.001 mg/kg body weight, preferably at least 0.01 mg/kg body weight, more preferably at least 0.1 mg/kg body weight, and up to about 100 mg/kg body weight, preferably up to about 20 mg/kg body weight, more preferably up to about 1 mg/kg body weight for a patient weighing about 75 kg. The dose may be administered in a single dose or divided into several doses (e.g. two, three or four times). Especially in the treatment of acute heart rate abnormalities, parenteral injection or infusion, for example in a unit of intensive protection, for example by intravenous continuous infusion, is preferred.

Compounds of formula (I) and their physiologically tolerated salts selectively inhibit K⁺(cAMP) channel and I_KsA channel. By virtue of this property, in addition to their use as pharmaceutically active compounds in human or veterinary medicine, they can also be used as scientific tools or adjuvants for biochemical studies in which they act on potassium channel generationIt may also be used for diagnostic purposes, e.g. for in vitro diagnosis of cell or tissue samples. As mentioned above, they can also be used as intermediates for the preparation of other pharmaceutically active compounds.

Abbreviations used herein DMA Dimethylacetamide HMPT hexamethylphosphoramide TMU Tetramethylurea Hr h M N M N O N O N O N O N

Example 1: ethanesulfonic acid (3-hydroxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3, 2-c)]Pyridin-4-yl) methylamides

A solution of 480 mg (3.5 mmol) of N-methylethylsulfonamide in 0.75 ml of DMSO (dimethyl sulfoxide) is added to a suspension of 27 mg (0.7 mmol) of NaH (60% strength) in 1.5 ml of DMSO. After stirring for 2 hours at room temperature, a solution of 0.48 g (2.7 mmol) of 2, 2-dimethyl-1 a,7 b-dihydro-2H-1, 3-dioxa-6-aziridino [ a ] naphthalene (prepared analogously as described in G.Burell et al, J.Med.chem., 33(1990) 3023-3027) in 6 ml of DMSO is added dropwise. The mixture was heated at 60 ℃ for 4 hours and then stirred at room temperature overnight. The reaction mixture was added to ice water, and extracted with ethyl acetate. After removal of the solvent in vacuo, the resulting solid was stirred with a mixture of heptane and ethyl acetate and filtered with suction. 400 mg (67%) of ethanesulfonic acid (3-hydroxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-c ] pyridin-4-yl) methylamide were obtained as a solid (m.p. 163 ℃ C.).

Claims (20)

1. Compounds of formula (I) and physiologically tolerated salts thereofWherein

R (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

or

R (1) and R (2) together are an alkylene chain having 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms;

in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (3) is R (12) -C_aH_2a[NR(13)]_m-；

R (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇；

a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10;

m is 0 or 1;

r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms;

or

R (12) and R (13) together are alkylene having 4, 5, 6, 7 or 8 carbon atoms,

in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, - [ SO ]_{0.1 or 2}]-, -CO-or-NR (10) -;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (4) is R (14) -C_rH_2r；

r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino;

wherein at C_rH_2rOne CH of the radicals₂The radical may beIs interrupted by-O-, -CH = CH-, -C ≡ C-, -CO-O-, -CO-NR (11) -, - [ SO ≡ C ]_{0.1 or 2}]-, or-NR (11) -substitution;

r (11) is hydrogen or- (C)_aH_2a)-R(10)；

Wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or R (3) and R (4) together are an alkylene group having 3,4, 5, 6, 7 or 8 carbon atoms,

in which one CH is present in the alkylene chain₂The radicals may be substituted by-O-, - [ SO ]_{0.1 or 2}]-, -CO-or-NR (11) -;

r (11) is hydrogen or- (C)_aH_2a)-R(10)，

Wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (5) and R (6) are

-CR(15)=CR(16)-CR(17)=N-,

-CR(15)=CR(16)-N=CR(17)-,

-CR(15)=N-CR(17)=N-,

-CR(15)=N-N=CR(17)-,

-N = CR (16) -CR (17) = N-or

-S-CR(15)=CR(16)-；

R (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or a phenyl group,

which are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl,Br、I、CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;

r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR(19)R(20)；

Wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

u is 2 or 3;

r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

s is 0, 1, 2, 3,4, 5 or 6;

z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO_{(0, 1 or 2)}-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-；

R (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3 or 4 carbon atoms, acyloxy having 1, 2, 3 or 4 carbon atoms, Cl, Br, F, alkyl having 1, 2, 3 or 4 carbon atoms;

r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

2. Compounds of formula i according to claim 1, in which:

r (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

or

R (1) and R (2) together are an alkylene group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms;

in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (3) is R (12) -C_aH_2a[NR(13)]_m-；

R (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇；

a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10;

m is 0 or 1;

r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms;

r (4) is R (14) -C_rH_2r；

r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino;

wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution;

r (11) is hydrogen or- (C)_aH_2a)-R(10)；

Wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution;

a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10; r (5) and R (6) are

-CR(15)=CR(16)-CR(17)=N-,

-CR(15)=CR(16)-N=CR(17)-,

-CR(15)=N-CR(17)=N-,

-CR(15)=N-N=CR(17)-,

-N = CR (16) -CR (17) = N-or

-S-CR(15)=CR(16)-；

R (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;

r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR(19)R(20)；

u is 2 or 3;

r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl;

r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

s is 0, 1, 2, 3,4, 5 or 6;

z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-；

R (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3 or 4 carbon atoms, acyloxy having 1, 2, 3 or 4 carbon atoms, Cl, Br, F, alkyl having 1, 2, 3 or 4 carbon atoms;

r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

3. Compounds of formula i according to claims 1 or 2, wherein:

r (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

or

R (1) and R (2) together are an alkylene group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms;

in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (3) is R (12) -C_aH_2a[NR(13)]_m-；

R (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇；

a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10;

m is 0 or 1;

r (13) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms;

r (4) is R (14) -C_rH_2r；

r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino;

wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution;

r (11) is hydrogen or- (C)_aH_2a)-R(10)；

Wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution;

r (5) and R (6) are

-CR (15) = CR (16) -CR (17) = N-or

-CR(15)=CR(16)-N=CR(17)-；

R (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Substituent of methyl, methoxy, sulfonylamino and methylsulfonylGeneration;

r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;

r (21) is hydrogen, methyl, ethyl, phenyl or-C_uH_2u-NR(19)R(20)；

u is 2 or 3;

r (20) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl;

r (22) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, -COOR (21), CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl;

s is 0, 1, 2, 3,4, 5 or 6;

z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-；

R (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3, or 4 carbon atoms, alkyl having 1, 2, 3, or 4 carbon atoms;

r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

4. A compound of formula i according to claims 1, 2 or 3, wherein:

r (1) and R (2) independently of one another are hydrogen, CF₃、C₂F₅、C₃F₇Alkyl or phenyl having 1, 2, 3,4, 5 or 6 carbon atoms,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Preparation of methyl, methoxy, sulfonamido and methanesulfonylSubstituent groups;

or

R (1) and R (2) together are an alkylene group having 2, 3,4, 5 or 6 carbon atoms;

in which one CH of the alkylene chain is₂The radicals may be substituted by-O-, -CO-, -S-, -SO-, -SO₂-or-NR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (3) is R (12) -C_aH_2a-；

R (12) is hydrogen or cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CF₃、C₂F₅Or C₃F₇；

a is 0, 1, 2, 3,4, 5, 6, 7, 8, 9 or 10;

r (4) is R (14) -C_rH_2r；

r is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or 13;

r (14) is hydrogen, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF₃、C₂F₅、C₃F₇Pyridyl, thienyl, imidazolyl or phenyl,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido, methanesulfonyl and methanesulfonylamino;

wherein at C_rH_2rOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -CO-NR (11) -, - [ SO ]_{0.1 or 2}]-or-NR (11) -substitution;

r (11) is hydrogen or- (C)_aH_2a)-R(10)；

Wherein at C_aH_2aOne CH of the radicals₂The groups may be substituted by-O-, -CH = CH-, -C.ident.C-, -CO-O-, -O-CO-, -S-, -SO-, -SO ≡ C-, -C ≡ C-, -CO-O-, -O-CO-, -S-, -SO-, -C-O-C-O-₂-, NR (10) -or-CONR (10) -substitution;

r (10) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r (5) and R (6) are

-CR (15) = CR (16) -CR (17) = N-or

-CR(15)=CR(16)-N=CR(17)-；

R (15), R (16) and R (17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms, CN, CF₃、C₂F₅、C₃F₇、N₃、NO₂、-CONR(19)R(21)、-COOR(21)、R(22)-C_sH_2s-Z-or a phenyl group,

they are unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido and methanesulfonyl;

r (19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;

r (21) is hydrogen, methyl, ethyl or phenyl,

wherein the phenyl group is unsubstituted or substituted by 1 or 2 groups selected from F, Cl, Br, I, CF₃Methyl, methoxy, sulfonamido or mesyl;

r (22) is hydrogen;

s is 0, 1, 2, 3,4, 5 or 6;

z is- [ S (O)_{0.1 or 2}]-、-CO-、-SO₂-NR(11)-、-SO₂-O-, -NR (11) -or- [ CO-NR (11)]-；

R (7) is hydrogen, hydroxy, alkoxy having 1, 2, 3, or 4 carbon atoms, alkyl having 1, 2, 3, or 4 carbon atoms;

r (8) is hydrogen or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

5. A process for the preparation of the compounds of the formula I as claimed in one or more of claims 1 to 4, which comprises

a) The compounds of the formula II are reacted in a manner known per se

Wherein R (1), R (2), R (5), R (6), R (7) and R (8) have the above-mentioned meanings and L is a conventional nucleofugic leaving group, in particular F, Cl, Br, I,MeSO₂-O-, p-toluenesulfonyloxy, or R (7) and L together are an epoxide ring,

with sulfonamides of the formula III or salts thereof

Wherein R (3) and R (4) have the above-mentioned meanings, M is hydrogen or a preferably equivalent metal, preferably lithium, sodium or potassium;

or

b) Reacting a compound of formula IVWherein R (1), R (2), R (4), R (5), R (6), R (7) and R (8) have the abovementioned meanings, with sulfonic acid derivatives of the formula V

Wherein R (3) has the above-mentioned meaning and W is a nucleofugic leaving group, such as fluorine, bromine, 1-imidazolyl, but preferably chlorine;

or

c) The compounds of the formula VI are reacted under alkylation conditions in a manner known per se

Wherein R (1), R (2), R (3), R (5), R (6), R (7), R (8) and M have the above-mentioned meanings,

with alkylating agents of the formula VII

R(4)-L Ⅶ

Wherein R (4) is not hydrogen and L has the above-mentioned meaning;

or

d) If at least one of the R (15), R (16), R (17) positions on the ring systems R (5) to R (6) is hydrogen and the other substituents R (1) to R (8) have the abovementioned meaning, electrophilic substitution is carried out in at least one of the R (15), R (16), R (17) positions of the ring systems R (5) to R (6) of the compounds of the formula I

Wherein R (1) to R (4), R (7) and R (8) have the above-mentioned meanings.

6. A compound of the formula i as claimed in one or more of claims 1 to 4 or a physiologically tolerated salt thereof for use as a medicament.

7. A pharmaceutical preparation which comprises an effective amount of at least one compound of the formula i according to one or more of claims 1 to 4 and/or of a physiologically tolerable salt thereof as active compound, together with pharmaceutically acceptable excipients and additives and, if desired, one or more further pharmacologically active ingredients.

8. Use of compounds of the formula I as claimed in one or more of claims 1 to 4 and/or their physiologically tolerated salts for the production of compounds having K⁺Channel blocking effect for the treatment and prevention of K⁺Use of a medicament for a channel-mediated disease.

9. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerable salts for the production of medicaments for the treatment or prophylaxis of arrhythmias which can be ruled out by a potentially prolonged action.

10. The use of a compound i according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of atrial fibrillation or atrial flutter.

11. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerated salts for the production of medicaments for inhibiting gastric acid secretion.

12. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerable salts for the production of medicaments for the treatment or prophylaxis of gastric or intestinal ulcers.

13. The use of a compound of the formula i as claimed in one or more of claims 1 to 4 and/or of a physiologically tolerable salt thereof for producing a medicament for the treatment or prophylaxis of gastroesophageal inflammation.

14. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerable salts for the production of medicaments for the treatment or prophylaxis of diarrhea.

15. The use of a compound of the formula i as claimed in one or more of claims 1 to 4 and/or of a physiologically tolerable salt thereof for the production of a medicament for the therapy or prophylaxis of all types of arrhythmia, including atrial, ventricular and supraventricular arrhythmias.

16. The use of a compound of the formula i as claimed in one or more of claims 1 to 4 and/or of a physiologically tolerable salt thereof for producing a medicament for the treatment or prophylaxis of reentry arrhythmias or for the prevention of sudden cardiac death due to ventricular fibrillation.

17. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerable salts for the production of medicaments for the treatment of cardiac insufficiency, in particular heart failure.

18. The use of compounds of the formula i as claimed in one or more of claims 1 to 4 and/or their physiologically tolerable salts for blocking calcium channels which are opened by cyclic adenosine monophosphate (cAMP).

19. The use of a compound of the formula i as claimed in one or more of claims 1 to 4 and/or of a physiologically tolerated salt thereof for the production of a medicament for inhibiting irritating gastric acid secretion, for the treatment or prophylaxis of gastric or intestinal ulcers, of gastroesophageal inflammation, of diarrhoea, for the treatment or prophylaxis of cardiac arrhythmias, including atrial, ventricular or supraventricular arrhythmias, atrial fibrillation and atrial flutter and reentrant arrhythmias, or for the prophylaxis of sudden cardiac death due to ventricular fibrillation.

20. A therapeutic agent comprising an effective amount of a compound of formula i as claimed in claims 1-4.