MXPA98006267A - Substituted compounds with sulfonamide, procedure for its preparation, its use as a diagnostic medicine or agent as well as a medicine that contains them - Google Patents

Abstract

Compounds of the formula I (See formula) with the meanings of the substituents indicated in the claims, are outstandingly active substances for the preparation of medicaments intended for the prophylaxis and therapy of cardio-circulatory diseases, especially arrhythmias, for the Treatment of ulcers of the gastro-intestinal zone or for the treatment of diarrheal diseases

Description

Compounds substituted with suifonamide, process for its preparation, its use as a medicine or diagnostic agent as well as medicine containing them The invention relates to compounds of the formula I wherein R (l), R (2), R (3), R (4), R (5), R (6), R (7) and R (8) have the meanings indicated in the following , its preparation and its use, especially in medicines. The compounds influence the open potassium channel by cyclic adenosine monophosphate (cAMP) or the IKs channel, and are outstandingly suitable as active medicinal substances, for example for the prophylaxis and therapy of cardio-circulatory diseases, especially arrhythmias, for the treatment of ulcers of the gastro-intestinal region or for the treatment of diarrheal diseases. In the chemistry of drugs, the class of 4-acylamino-chroman derivatives has been intensively studied in recent years. The most prominent representative of this class is Cro a alim, of formula A. ("Chem. Soc. Perkin Trans. 1, 1991, 63 -70).

In the case of Cromakalim and other related derivatives of 4-acylamino-crómanos are compounds with relaxing effect on smooth muscle organs, so that they can be used to reduce high blood pressure as a result of relaxation of vascular muscles, and in the treatment of asthma as a consequence of the relaxation of the smooth muscles of the respiratory tract. It is common to all these preparations that they act in the cellular plane of for example smooth muscle cells and lead there to an opening of certain K + channels sensitive to ATP. The increase of the negative electric charge in the cell (hyperpolarization), which has been induced by the exit of K + ions, counteracts through secondary mechanisms the increase of the intracellular concentration of Ca + and consequently a cellular activation, which leads p. ex. to a contraction of the muscles. Structures similar to those of formula I, the so-called pyranopyridines (formula B), have been described in the literature. However, these are also exclusively derivatives of 4-acylamino, which also have blocking properties of the K-ATP channels. Of these acylamino derivatives, the compounds of the formula I, according to the invention, differ structurally, inter alia, by replacing the acylamino group with a sulfonylamino function. While Cromakalim (formula A) and acylamino compound analogs act as ATP-sensitive K + channel openers, the compounds of the formula I with the sulfonylamino structure according to the invention, however, have no opening effect on this channel. K + (ATP), but surprisingly manifest an intense and specific blocking effect (closer) on a K + channel, which had been opened by cyclic adenosine monophosphate (cAMP), and is fundamentally different from the above-mentioned K + channel (ATP).

More recent investigations have shown that this K + channel (cAMP) identified in the tissue of the large intestine is very similar, possibly even identical, to the IKs channel identified in the cardiac muscle (myocardium). In fact, for the compounds according to the invention, could show an intense blocking effect on the channel of IKs in guinea pig cardiomyocytes as well as on the IsK channel expressed in Xenopus oocytes. As a consequence of this blocking of the K + channel (cAMP) or the IK channel, the compounds according to the invention develop in a living organism pharmacological effects of high therapeutic utility. The invention concerns compounds of the formula I wherein they mean: R (l) and R (2) independently of one another, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5, or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (l) and R (2) in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms; wherein a CH2 group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO-, -S02- or -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) (12) -CaH2a [N (13)] m-; R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m zero or 1; R (13) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (12) and R (13) in common, an alguileno group with 4, 5, 6, 7 or 8 atoms of C, being able a group CH2 of the alkylene group to be replaced by -O-, "[SOcero, 1 6 2-1- '-C0"° -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (4) R (1, 4) -CrH2r; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group which consists of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; whereby a CH2 group of the CrH2r group can be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [S0cer? / i 6 2] - OR -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10); a CH2 group of the CaH2a group can be replaced by -O-, -CH = CH-, -C = C-, -CO-, 10 -CO-O-, -O-CO-, -S-, -SO- , -S02-, -NR (10) - or ene or alkyl with 1, 2 or 3 C atoms; or 15 R (3) and R (4) in common, an alkylene chain with 3, 4, 5, 6, 7 or 8 C atoms, being able a CH2 group of the alkylene chain to be replaced by -O-, - [SOcer? Í -_ or 2J ~ ". -CO- or 20 -NR (ll) -; R (ll) hydrogen or -CaH2a-R (l0), a CH2 group of the CaH2a group being able to be replaced by -O -, -CH = CH-, -C = C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S02-, -NR (10) -O 25 -CONR (10) -; R (10) hydrogen or alkyl with 1, 2 or 3 carbon atoms; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N -, 30 -CR (15) = CR (16) -N = CR (17) -, -CR (15) = N-CR (17) = N-, -CR (15) = NN = CR (17) -, -N = CR (16) -CR (17) == N- or -S-CR (15) = CR (16) -; 35 R (15), R (16) and R (17) independently one from another, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl pSF ^ with 3, 4, 5, 6, 7 or 8 C atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -COOR (21), R (22) -C3H2s-Z- or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (21) hydrogen, methyl, ethyl, phenyl or -CuH2u-NR (19) R (20); phenyl being unsubstituted or # substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, R (20) hydrogen or alkyl with 1, 2 or 3 C atoms, or 2 or 3, - 20 R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -COOR (21), -CONR (19) (21) , thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of group consisting of F, Cl, Br, I,. CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; s zero, 1, 2, 3, 4, 5 or 6; Z - [S (0) cer? F! or 2] -, -CO-, -SO (0 / or 2) -NR (ll) -, -S02-0-, -O-, -NR (ll) - or - [CO-NR (ll)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, Acyloxy with 1, 2, 3 or 4 C atoms, Cl, Br, F, alkyl with 1, 2, 3 or 4 C atoms; R (8) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; and their physiologically compatible salts. Preferred are compounds of formula I, in which they mean: R (l) and R (2) 5 independently of one another, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, ulfamoyl and methylsulfonyl; in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 15 8, 9 or 10 C atoms, being able a CH2 group of the alkylene chain to be replaced by -0-, -CO-, -S-, -SO-, -S02- or -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a [NR (13)] m-; 20 R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; x to zero or 1; R (13) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; R (4) R (14) -CrH2r; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group Which comprises F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; being able a CH2 group of the CrH2r group to be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [S0cer? / 1 6 21- or -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10) being able a CH2 group of the CaH2a group to be replaced by -0-, -CH = CH-, -Cs = C- / "" • CO-, -CO- o-, -O-CO-, -s- / • SO- / ~ -so2-, -NR (10) OR -CONR (10) - / zero, 1, 2, 3,, 4, 5., 6 , 7, 8, 9 10; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N-, -CR (15) = CR (16) -N = CR (17) -, -CR ( 15) = N-CRÍ17) = N-, -CR (15) = NN = 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, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -C00R (21), R (22) -C3H2s-Z- or phenyl, which is replace or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, • sulfamoyl and methylsulfonyl; R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (21) hydrogen, methyl, ethyl, phenyl or -CuH 2u-NR (19) R (20); u 2 or 3; R (20) hydrogen or alkyl having 1, 2 or 3 carbon atoms; the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl or methylsulfonyl; R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -C00R (21), -CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl , 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5 or C3F7 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3 , methyl, methoxy, sulfamoyl or methylsulfonyl; s zero, 1, 2, 3, 4, 5 or 6; Z - [S (0) cer? /? or 2] -, -CO-, -SO-NR (ll) -, -S02-0-, -0-, -NR (II) - or - [CO-NR (II)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, acyloxy with 1, 2, 3 or 4 C atoms, Cl, Br, F, alkyl with 1, 2, 3 or 4 atoms of C; R (8) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms, and their physiologically compatible salts. Especially preferred are compounds of formula I, in which they mean: R (l) and R (2) independently of one another, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, or R (l) and R (2) in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms; being able a CH2 group of the alkylene chain to be replaced by -O-, -CO-, -S-, -SO-, -S02- OR -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a [NR (13)] m-; R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m zero or 1; R (13) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (4) R (14) -CrH2r; r 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; being able a CH2 group of the CrH2r group to be replaced by -0-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (II) -, - [S0cer? / ? & 2] - or -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10), a CH2 group of the CaH2a group being able to be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O -, -O-CO-, -S-, -SO-, -S02-, -NR (10) - or -CONR (10) -; R (5) and R (6) -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, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -C00R (21), R (22) -C3H2s-Z- or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from group 5 consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (21) hydrogen, methyl, ethyl, phenyl or -CuH 2u-NR (19) R (20); 10 or 2 or 3; R (20) hydrogen or alkyl having 1, 2 or 3 C atoms; • # the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulphamoyl or methylsulfonyl; R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -C00R (21), -CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, or C3F7 or phenyl,. which is unsubstituted or substituted with 25 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, • • s zero, 1, 2, 3, 4, 5 or 6; 30 Z - [S (0) zero tld 2] -, -CO-, -S02-NR (11) -, -S02-0-, -O-, -NR (ll) - or - [CO-NR ( ll)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, alkyl having 1, 2, 3 or 4 C atoms; R (8) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; 35 and its physiologically compatible salts. Especially preferred are the compounds of the formula I, in which they mean: laced by -0-, -CH = CH-, -C = C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S02-, -NR (10 ) - or -CON (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 C atoms; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N- or -CR (15) = CR (lß) -N = CR (17) -; R (15), R (16) and R (17) 10 independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl with 3, 4, 5 , 6, 7 or 8 C atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -COOR (21), R (22) -C3H2s-Z- or phenyl, Which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R (19) hydrogen or alkyl having 1, 2 or 3 atoms of 20 C; R (21) hydrogen, methyl, ethyl or phenyl, the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R (22) hydrogen; s zero, 1, 2, 3, 4, 5 or 6; «Z -tS (0) cßr? Fx or 21 -, -CO-, -S02-NR (1D-, 30 -S02-0-, -O-, -NR (ll) --O - [CO-NR ( ll)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 carbon atoms, alkyl with 1, 2, 3 or 4 carbon atoms; R (8) hydrogen or alkyl with 1, 2 , 3, 4, 5 or 6 C atoms, and physiologically compatible salts thereof If the compounds I contain an acidic or basic group or a basic heterocycle, the corresponding pharmacological and toxicological salts are also subject of the invention. - 14 - compatible. Thus, the compounds I, which carry one or more groups -COOH, can be used, for example, as alkali metal salts, preferably as sodium or potassium salts. The compounds I, which carry a basic protonatable group or a basic heterocyclic group, can also be used in the form of their salts by addition of organic acids 0 inorganic, pharmacologically and toxicologically compatible, for example in the form of hydrochlorides, methanesulfonates, acetates, lactates, maleates, fumarates, maleates, gluconates, etc. If the compounds I contain an acid group and a basic group in the same molecule, they belong to the invention, together with the forms of salts that have been pointed out, also internal salts, the so-called betaines. The compounds of the formula I can be presented in stereoisomeric forms, in case they have a corresponding substitution. If the compounds of the formula 1 contain one or more centers of asymmetry, these can have, independently of one another, the configuration S or the configuration R. All the features of the invention belong to the invention. possible forms of stereoisomers, p. ex. enantiomers or diastereoisomers, and mixtures of two or more stereoisomeric forms, e.g. ex. enantiomers and / or diastereoisomers, in any ratios. The subject of the invention are the p-enantiomers. ^^ ex. consequently in pure form as regards the enantiomers, as antipodes both left-handed and also dextrorotatory, and also in the form of mixtures of both enantiomers in different ratios or in the form of racemates. In the case of presenting a cis / trans isomerism, both the cis-form and the trans-form and mixtures thereof are the object of the invention. these forms. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture according to customary methods or p. ex. by stereoselective synthesis. In the case of mobile hydrogen atoms, the present invention also encompasses all The tautomeric forms of the compounds of formula I. The alkyl and alkylene radicals may be linear or branched. - 15 - # The compounds of the formula I can be prepared by different chemical processes, which are also part of the invention. Thus, a compound of the formula I, 5 a) is obtained by reacting a compound of the formula II in a manner known per se. in which R (l), R (2), R (5), R (6), R (7) and R (8) have the indicated meanings and L means a usual nucleophilic leaving group, especially F, Cl , Br, I, MeS02 -0-, a p-toluenesulf onyloxy radical, or R (7) and L are in common a ring of Epoxide, with a sulfonamide or one of its salts of the formula III wherein R (3) and R (4) have the indicated meanings and 30 M represents hydrogen or preferably one equivalent of a metal, particularly preferably lithium, sodium or potassium; or because 35 b) a compound of the formula IV is reacted - 16 - * wherein R (l), R (2), R (4), R (5), R (6), R (7) and R (8) have the indicated meaning, with a sulfonic acid derivative of the formula V Wherein R (3) has the indicated meaning and means a nucleophobic leaving group, such as fluoro, bromo or 1-imidazolyl, but especially chloro; Or because c) a compound of the formula VI is reacted in a manner known per se. wherein R (l), R (2), R (3), R (5), R (6), R (7), R (8), and M have the indicated meanings, with an alkylating agent - 35 tion of the formula VII R (4) -L VII in the sense of an alkylation reaction, in which R (4) - 17 - with the exception of hydrogen as well as L possess the indicated meanings; or because d) in a compound of the formula I in which R (l) to R (4), R (7) and R (8) have the indicated meanings, an electrophilic substitution reaction is carried out in at least one of the positions R (15), R (16), R (17) of the ring system R (5) -R (6), as long as this position means hydrogen and the remaining substituents R (l) to R (8) have the meanings indicated.

Method a) describes the reaction of a sulfonamide or one of its salts of the formula III with a reactive heterocycle of the formula II. Since the reaction of a sulfonamide III is carried out from the salt form, in the case of using a free sulfonamide (formula III, M = H) by the action of a base, a sulfonamide salt (formula III, M = cation) must be generated, which is distinguished by a higher nucleophilicity and therefore for a higher reactivity. If a free sulfonamide (M = H) is used, the deprotonation of the sulfonamide to form the salt is carried out in situ with the preferential use of those bases, which by themselves are not alkylated or are only slightly alkylated, such as sodium carbonate. , potassium carbonate, an amine strongly hindered sterically, p. ex. dicyclohexylamine, - 12 - R (l) and R (2) independently of each other, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, or R (l) and R (2) in common, an alkylene chain with 2 , 3, 4, 5 or 6 C atoms; wherein a CH2 group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO-, -S02- OR -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a-; R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (4) R (14) -CrH2r; r 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2, substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; can a CH2 group of the CrH2r group be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [S0cer ?? ? or 2] - or -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10), with a CH2 group of the CaH2a group N, N, N-dicyclohexyl-ethylamine or other nitrogenous bases * strong with low nucleophilicity, for example DBU, N, N ', N' '' - triisopropyl-guanidine, etc. However, other commonly used bases, such as tere, can also be used for the reaction. potassium butylate, sodium methylate, alkali metal hydrogen carbonates, alkali metal hydroxides, such as for example LiOH, NaOH or KOH, or alkaline earth metal hydroxides, for example Ca (0H) 2. In this case, preferably work is carried out within the polar organic solvents, such as dimethyl formamide, dimethyl acetamide, tetramethyl urea, hexamethyl triamide * phosphoric acid, tetrahydrofuran, dimethoxyethane, toluene, a halogenated hydrocarbon, such as chloroform or methylene chloride, etc. In principle, however, you can work Also in polar protic solvents, such as water, methanol, ethanol, isopropanol, ethylene glycol or their oligomers, and their corresponding semi ethers and ethers. The reaction is carried out in a preferred temperature range of -10 to 140 ° C, particularly preferably in the from 20 to 100 ° C. In a favorable manner, the procedure mode a) can also be carried out under the conditions of a two-phase catalysis. The compounds of formula II are obtained in accordance # with known methods from the literature, for example from the corresponding unsaturated compound X by the action of an inorganic or organic peroxide, such as for example H202, MCPBA or peracetic acid. The reaction by addition of halogen / OH is also possible by the reaction of X with NCS, NBS, chlorine or bromine in aqueous solvents. In the case of the epoxide [R (7) and L form an epoxide ring] this can be prepared from the hydrohalogenide by separation of H-halogen with different bases. Advantageously, it is worked in a solvent, which is sufficiently inert against these halogenating or oxidizing reagents, such as, for example, in DMSO or halogenated hydrocarbons, such as p. ex. chloroform or methylene chloride. Process mode b) describes the known and frequently used reaction of a reactive sulfonyl compound of the formula V, especially a chlorosulfonyl compound (= Cl) with An amino derivative of the general formula IV to form the corresponding sulfonamide derivative of the general formula I. The reaction can be carried out in principle without any solvent, but such reactions are carried out in most cases using a dissolvent 20. The reaction is preferably carried out using a polar solvent, preferably in the presence of a base, which by itself can be advantageously used as a solvent, e.g. ex. in the case of using triethylamine, especially in the presence of pyridine and its homologs. Solvents also used are, for example, water, aliphatic alcohols, e.g. ex. methanol, ethanol, isopropanol, sec. -butanol, ethylene glycol and its monoalkyl ethers and dialkyl ethers monomers and oligomers, tetrahydrofuran, Dioxane, dialkylated amides such as DMF, DMA, as well as TMU and HMPT. In this case, the process is carried out at a temperature of 0 to 160 ° C, preferably 20 to 100 ° C. The amino derivatives of the formula IV are obtained in a manner known per se from the literature, preferably by reaction of the compounds reagents of the formula II in which R (l), R (2), R (5), R (6) and L have the indicated meanings, either with ammonia or with an amine of the formula XI - ^ R (4) -NH2 XI in which R (4) has the indicated meaning.

Mode c) of process 5 represents the alkylation reaction, known per se, of a sulfonamide or one of its salts VI with an alkylating agent of the formula VII. Corresponding to the analogy of reactions with procedure mode a), the conditions of procedure are valid for mode c) reactions already described in detail when referring to procedure mode a). ^^? The preparation of the sulfonamide VI derivatives and their precursor products was already described in the case of process mode b). The preparation of the alkylating agents VII is carried out in accordance with analogous prescriptions of the literature or as described for process mode a), preferably from the corresponding compounds with hydroxy (formula VII in which L is equal to -OH). Process mode d) describes the further chemical conversion of compounds of the formula I according to the invention, in other compounds of the formula I, by electrophilic substitution reactions in a or several of the positions designated by R (5) to R (8), which in each case mean hydrogen. Preferred substitution reactions are 1. aromatic nitration for the introduction of one or more nitro groups, as well as the subsequent reduction of This or these to form NH2-, 2. aromatic halogenation especially for the introduction of chlorine, bromine or iodine, 3. chlorosulfonation for the introduction of a chlorosulfonyl group by the action of chlorosulfonic acid, 4. the acylation reaction of Friedel-Crafts for the introduction of an acyl radical according to methods known from the literature.

In all modes of procedure, it may be appropriate to provisionally protect functional groups in the molecule in the case of certain steps of the reaction. Such techniques with protective groups are usual for a person skilled in the art. The choice of a protective group for groups that come into consideration and the procedures for their introduction and separation, have been described in the literature and can eventually be adapted without difficulty to each individual case. It has already been said that the compounds of the formula I surprisingly have a strong and specific blocking (closing) effect on a K + channel, which had been opened by * cyclic adenosine monophosphate (cAMP) and which differs fundamentally from the well-known K ~ (ATP) channel, and which This K + channel (cAMP) identified in the tissue of the large intestine is very similar, possibly even identical, to the channel of IKs identified in the cardiac muscle (myocardium). For the compounds according to the invention, a strong blocking effect on the channel of IKs could be demonstrated in guinea pigs as well as on the IsK channel expressed in Xenopus oocytes. As a consequence of this blocking of the K + channel (cAMP) or the IK channel, the compounds according to the invention develop pharmacological effects of high therapeutic use in the living organism and are outstandingly suitable as active medicinal substances for the therapy and the prophylaxis of different clinical pictures and symptomatology. Thus, the compounds according to the invention of the formula I are distinguished as a new class of active substances from potent inhibitors of stimulated gastric acid secretion. The compounds of the formula I are therefore valuable active pharmaceutical substances for the therapy and prophylaxis of ulcers of the stomach and the intestinal region, for example of the duodenum. They are also appropriate, as a consequence of its strong inhibitory effect on the secretion of gastric juices, as excellent therapeutic agents for the therapy and prophylaxis of esophagitis ^^ r reflux. The compounds according to the invention of the formula I are further distinguished by an antidiarrheal effect and are therefore suitable as active medicinal substances for the therapy and the prophylaxis of diarrheal diseases. In addition, the compounds of the formula I according to the invention are suitable as active medicinal substances for the therapy and prophylaxis of cardio-circulatory diseases. Especially, these can be used for the therapy and the prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, especially of heart rhythm disorders, which can be resolved by prolonging the action potential. therapy and prophylaxis of atrial fibrillation (atrial fibrillary arrhythmia) and atrial flutter (atrial flutter) as well as for the therapy and prophylaxis of reentry arrhythmias (reentry) and for the avoidance of sudden cardiac death as a consequence of ventricular fibrillation. Even though numerous substances with an antiarrhythmic effect are already on the market, there is no compound that is actually satisfactory in terms of activity, the range of applications and the profile of side effects, so that there is still a 25 a need to develop improved antiarrhythmic agents. The effect of numerous known antiarrhythmic agents of the so-called class III is based on an increase in the refractory myocardial time period by prolongation of the duration of the action potential. This is essentially determined by the magnitude of the repolarizing K + currents, which leave the cell through different K + channels. It is attributed in this case an especially great importance to the so-called l? "retarded rectifier, of the English 35 delayed rectifier", of which there are two subtypes, a rapidly activated IKr and a slowly activated IKs. Most of the known antiarrhythmic agents of class III ft block predominantly or exclusively to IKr (eg Dofetilid and d-Sotalol). However, it has been shown that these compounds, with small or normal heart rates, present an increased proarrhythmic risk, especially arrhythmias, which are termed "Torsades de Pointes" (DM Roden; "Current Status of Class"). III Antiarrhytmic Drug Therapy "; Am. J. Cardiol. 72 (1993), 44 B-49 B). With higher heart rates or respectively with stimulation of the β-10 receptors, on the contrary, the prolonged effect of the action potential of the IKr blockers is clearly reduced, which is attributed to the fact that in these conditions the IKs contribute in greater degree to repolarization. For these reasons, the substances according to the invention, that act as blocking agents of IKs, present essential advantages compared to the known IKr blockers. In the meantime, it was also described that there is a correlation between the inhibitory effect of the IK channels and the repression of cardiac arrhythmias that threaten the Life, as caused by eg ß-adrenergic hyperstimulation (eg TJ Colatsky, CH Follmer and CF StaLrmer; "Channel Specif icity in Antiarrhytmic Drug Action; Mechanism of potassium channel block and i ts role in suppressing and aggravating cardiac arrhythmias "; Circulation 82 (1990), 2,235-2,242; A. E. Busch, K. Malloy, W. J. Groh, M.D. Varnum, J. P. Adelman and J. Maylie; "The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channel s in Xenopus oocytes and IKs in guinea pig cardiac myocytes"; Biochem. > Biophys. Res. Commun. 202 (1994), 265-270). In addition, the compounds contribute to a marked improvement of heart failure, especially of congestive heart failure (Congestive Heart Failure), advantageously in combination with active substances promoting contraction (positive inotropic), p. ex. fosf-gold-diesterase inhibiting agents. Despite the therapeutically useful advantages, which can be achieved by blocking the IKs, until now have described only very few compounds that inhibit this subtype of the "delayed rectifier". The substance Azimilide, which is in the development phase, certainly also has a blocking effect on the IKs, but predominantly blocks the IKr (selectivity 1:10). In the PCT patent document WO-A-95/14470 the use of benzodiazepines as selective blocking agents of IKs is claimed. Other IK blockers are described in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating IsK channels by chromanols ..." and Pflügers Arch. Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP -mediated Cl -secretion in rabbi t colon, acting by the reduction of cAMP- activated K7 conductance". However, the solubility in water of the compounds described therein is lower. The compounds of the formula I according to the invention and their physiologically compatible salts can therefore be used in an animal, preferably in a mammal, and especially in a human being, as medicinal products by themselves, in mixtures with each other or in the form of preparations pharmacists The present invention also relates to the compounds of the formula I and their physiologically compatible salts for their application as medicaments, their use in the therapy and the prophylaxis of the aforementioned clinical conditions and their use for the preparation of medicaments for these and of medicinal products with blocker effect of the K + channels. In addition, pharmaceutical preparations are prepared according to the present invention, containing as an active constituent an effective dose of at least one compound of the formula I and / or a physiologically compatible salt thereof together with conventional pharmaceutically irreproachable carriers and adjuvants. The pharmaceutical preparations normally contain from 0.1 to 90 weight percent of the compounds of the formula I and / or their physiologically compatible salts. The production of the pharmaceutical preparations can be carried out in a manner known per se. For this, the compounds of the formula I and / or their physiological salts compatible carriers are carried, together with one or more vehicle substances and / or solid or liquid galenic adjuvants and, when desired, in combination with other active medicinal substances, to an appropriate form of presentation or dosage form, which can then be use as medicine in human medicine or in veterinary medicine. The medicaments, which contain compounds according to the invention of the formula I and / or their physiologically compatible salts, can be applied orally, parenterally, e.g. ex. intravenous, rectal, inhalation or topical, the preferred application being dependent on each individual case, p. ex. of the respective clinical picture of the disease to be treated. To determine which coadjuvant substances are appropriate for the desired drug formulation is usual for a person skilled in the art by virtue of his knowledge of the specialty. In addition to solvents, gelling compounds, suppository bases, adjuvants for tablets and other vehicles of active substances, antioxidants, dispersing agents, emulsifiers, defoamers, flavor correctors, preservatives, solubilizers and agents for achieving an effect may be used. of deposit (delayed release), buffer substances or dyes. The compounds of the formula I for the attainment of an advantageous therapeutic effect can also be combined with other active drug substances. Thus, in the treatment of cardio-circulatory diseases, advantageous combinations with active substances on the circulation and the heart are possible. As such partners in combinations, which are advantageous for cardio-circulatory diseases, for example other antiarrhythmic agents, such as class I, class II or class III antiarrhythmic agents, such as for example IKr channel blockers, e.g. ex. Dofetilid, or in addition hypotensive substances, such as ACE inhibitors (for example ft Enalapril, Captopril, Ramipril), angiotensin antagonists, activators of K + channels, as well as blockers of alpha- and beta-receptors, but also sympathomimetic compounds with adrenergic action, as well as inhibitors of the exchange between Na + and H + , calcium channel antagonists, phosphorus-diesterase inhibitors and other substances with positive inotropic effect, such as p. ex. Digitalis glycosides or diuretic agents. In addition, combinations with active substances such as antibiotics and with antiulcer agents, for example with H2 antagonists (eg Ranitidine, Cimetidine, Famotidine, etc.), especially in the case of the application to the treatment of gastro-intestinal diseases. For an oral application form, the active compounds are mixed with the appropriate additive substances, such as vehicle substances, stabilizers or inert diluents, and are brought by the usual methods to the appropriate forms of presentation. , such as tablets, dragees, encapsulable capsules, aqueous, alcoholic or oily solutions. As inert vehicles, p. ex. gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the preparation can be carried out in the form of a dry granulate as well as that of a wet granulate. Suitable oily vehicle substances or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. As solvents for aqueous or alcoholic solutions enter in question p. ex. water, ethanol or sugar solutions or mixtures thereof. Other coadjuvant substances, also for other forms of application, are p. ex. polyethylene glycols and polypropylene glycols. For application subcutaneously or intravenously, the Active compounds, if desired together with the usual substances for this purpose, such as solubilizers, emulsifiers or other adjuvants, are brought into the form of a ft solution, suspension or emulsion. The compounds of the formula I and their physiologically compatible salts can also be lyophilized, and the lyophilized materials obtained can be used, for example. ex. for the production of preparations for 5 injection or infusion. Suitable solvents are p. ex. water, a physiological solution of sodium chloride or alcohols, p. ex. ethanol, propanol, glycerol, together with it also solutions of sugars, such as glucose or mannitol solutions, or also mixtures based on the different solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays, p. ex. solutions, suspensions or emulsions of the active substances of the formula I or their physiologically compatible salts in a pharmaceutically innocuous solvent, such as especially ethanol or water, or a mixture of such solvents. The formulation may also contain, as necessary, other pharmaceutical adjuvants such as surfactants, emulsifiers and stabilizers as well as a propellant gas. Such a preparation contains the active substance usually in a concentration of about 0.1 to 10, especially about 0.3 to 3 weight percent. The dosage of the active substance of the formula I Which is to be administered, or of the physiologically compatible salts thereof, depends on each individual case and has to be adapted, as is usual to obtain an optimum effect, to the particularities of each individual case. Thus, it naturally depends on the frequency of administration and of the intensity and duration of the effect of the compounds in each case used for therapy or prophylaxis, but also of the type and severity of the disease to be treated as well as sex, age, weight and capacity individual response of humans or animals that are to be treated, and if an acute or prophylactic therapy is performed. Usually, the daily dose of a compound of formula I, in the case of administration to a patient having a weight of about 75 kg, amounts to at least 0.001 mg / kg body weight, preferably at least 0.01 mg / kg body weight, especially at least 0.1 mg / kg body weight , up to a maximum of 100 mg / kg of body weight, preferably up to a maximum of 20 mg / kg of body weight, especially up to a maximum of 1 mg / kg of body weight. The dose can be administered in the form of a single dose, or it can be subdivided into several, eg. ex. two, three or. four, individual doses.

Especially in the case of the treatment of acute cases of heart rhythm disorders, for example in an intensive care stage, parenteral administration by injection or infusion, e.g. ex. by a permanent intravenous infusion. The compounds of the formula I and their physiologically compatible salts selectively inhibit the K + channels (cAMP) or the IK channels. By virtue of this property, they can be used, apart from as active medicinal substances in human medicine and in veterinary medicine, also as a scientific tool or as an adjunct agent for biochemical investigations, in which an influence on potassium channels is considered, as well as for diagnostic purposes, p. ex. in the in vitro diagnosis of cellular or tissue samples. In addition, as has already been As mentioned above, they can be used as intermediates for the preparation of other active medicinal substances.

Explanation of the abbreviations used in the text: 30 DMA dimethylacetamide HMPT hexamethyl triamide phosphoric acid TMU tetramethyl urea hour (s) 35 M mol (s) MCPBA m-chloroperbenzoic acid mM millimole (en) ft min minutes TEA triethylamine THF tetrahydrofuran NBS N-bromo-succinimide 5 NCS N-chlorosuccinimide.

Example 1: (3-Hydroxy-2, 2-dimethyl-3,4-dihydro-2H-pyrano [3,2-c] pyridin-4-yl) -methyl-ethanesulfonic acid amide To a suspension of 27 mg (0.7 mmol) of NaH (60%) in 1.5 ml of DMSO is added a solution of 480 mg (3.5 mmol) of N-methyl-ethylsulfonamide in 0.75 ml of DMSO (dimethylsulfoxide). After stirring for 2 h at RT, a solution of 0.48 g (2.7 mmol) of 2,2-dimethyl-7-dihydro-2H-1,3-dioxa-6-azazole is added dropwise. cyclopropa [a] naphthalene (prepared analogously to G. Burell et al., J. Med. Chem. 33 (1990) 3. 023 -3. 027) in 6 ml of DMSO. Heat for 4 h at 60 ° C and then allow to stir at RT overnight. The reaction mixture is poured onto ice-water and extracted with ethyl acetate. After having removed the After evaporation of the solvent in vacuo, the solid material obtained is stirred with a mixture of heptane and ethyl acetate and filtered with suction. 400 mg (67%) of the (3-hydroxy-2, 2-dimethyl-3,4-dihydro-2H-pyrano [3,2-c] pyridin-4-yl) -methyl-amide acid are obtained Ethanesulfonic acid as a solid material (mp 163 ° C).

Claims (4)

1. - Compounds of the formula I where they mean: R (l) and R (2) 15 independently of one another, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5, 0 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (l) and R (2) ft in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 25 8, 9 or 10 C atoms; wherein a CH2 group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO-, -S02- or -NR (10) -; 1 R (10) hydrogen or alkyl having 1, 2 or 3 C atoms; R (3) R (12) -CaH2a [NR (13)] m-, • R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 atoms of C, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 35 m zero or 1; R (13) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (12) and R (13) in common, an alkylene group with 4, 5, 6, 7 or 8 C atoms, wherein a CH2 group of the alkylene group can be replaced by -O-, -CSOcero. i d 2Í- * ~ 8 ~ or -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (4) R (14) -CrH2r; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; a CH2 group of the CrH2r group can be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [SOcer? / l or 2] - or -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10); wherein a CH2 group of the CaH2a group can be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S02-, -NR (10) - or -CONR (10) -; . R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R (3) and R (4) in common, an alkylene chain with 3, 4, 5, 6, 7 or 8 C atoms, with a CH2 group of the alkylene chain being able to be replaced by -O-, - [Scerocero? or 2] -, -CO- or -NR (ll) -; R (ll) hydrogen or -CaH2a-R (10), a CH2 group of the CaH2a group being able to be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S02-, -NR (10) - or -CONR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N-, -CR (15) = CR (16) -N = CR (17) -, -CR ( 15) = N-CR (17) = N-, -CR (15) = NN = 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, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -C00R (21), R (22) -C3H2s-Z- or phenyl, which is replacing or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (21) hydrogen, methyl, ethyl, phenyl or -CuH 2u-NR (19) R (20); the phenyl being unsubstituted or • substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, R (20) hydrogen or alkyl with 1, 2 or 3 atoms of C, or 2 or 3; R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, -C00R (21), -CON (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl , 1-pyrrolidinyl, 5-N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7 or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, 10 CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, • s zero, 1, 2, 3, 4, 5 or 6; Z -IS (0) cßr? / -. d 2] -, -CO-, -SO (0 /? or 2) -NR (ll) -, -S02-0-, -O-, -NR (ll) - or - [CO-NR (ll) ] -; 15 R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, acyloxy with 1, 2, 3 or 4 C atoms, Cl, Br, F, alkyl with 1, 2, 3 or 4 C atoms; R (8) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; and their physiologically compatible salts.

2. Compounds of the formula I according to claim 1, in which they mean: R (l) and R (2) independently of one another, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4 , 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; 30 or R (l) and R (2) in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, being able a CH2 group of the alkylene chain to be replaced by -O-, -CO-, 35 -S-, -SO-, -S02- or -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a [NR (13)] m-; ft R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m zero or 1; R (13) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; R (4) R (14) -CrH2r; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; 10 R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 ^ C atoms, piperidyl, 1-pyrrolidinyl, ^ r N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl , thienyl, imidazolyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; can a CH2 group of the CrH2r group be replaced by -0-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [SOcer? / xd 2J - ° -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10) ft > a group CH2 of group 25 CaH2a being able to be replaced by -0-, - CH = CH-, -C = C- / CO- / ~ * CO- 0-, -O- CO-, -s-, • SO - / "~ S02 ~~ / -NR (10) Ó -CONR (10) - zero, 1, 2, 3, 4, 5, 6,, 8, 9 30 10; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N- -CR (15) = CR (16) -N = CR (17) - CR (15) = N-CR (17) = N- , 35 CR (15) = NN = 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, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CN, CF3, C2F ?, C3F7, N3, N02, -CONR (19) R (21), -COOR (21), R (22) -C3H2s-Z- or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, - R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms C; R (21) hydrogen, methyl, ethyl, phenyl or -CuH2u-NR (i9) R (20); u 2 OR 3; R (20) hydrogen or alkyl having 1, 2 or 3 carbon atoms; the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulphamoyl or methylsulfonyl; R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -C00R (21), -CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl , 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5 or C3F7 or phenyl, which is unsubstituted or substituted with • 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl or methylsulfonyl; s zero, 1, 2, 3, 4, 5 or 6; Z "[S (0) cer? T or 2] -, -CO-, -SO-NR (ll) -, -S02-0-, -O-, -NR (ll) - or - [CO- NR (ll)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, acyloxy with 1, 2, 3 or 4 C atoms, Cl, Br, F, alkyl ft with 1, 2, 3 or 4 C atoms; R (8) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms, and their physiologically compatible salts.

3. Compound of the formula I according to claim 1 5 or 2, wherein R (l) and R (2) independently of one another mean hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3 , 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, • or 15 R (l) and R (2) in common, an alkylene chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms; wherein a CH2 group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO-, -S02- 20 O -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a [NR (13)] m-; R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, C2F5 or C3F7; 25 to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ta zero or 1; R (13) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (4) R (14) -CrH2r; 30 r 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group i comprising F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; whereby a CH2 group of the CrH2r group can be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (ll) -, - [S0cer? / -_ d 2] - or -NR (ll) -; R (ll) hydrogen or - (CaH2aJ -R (10), being able a CH2 group of the CaH2a group to be replaced by -O-, -CH = CH-, -C = C-, -CO-, 10 -CO-O -, -O-CO-, -S-, -SO-, -S02-, -NR (10) - O -CONR (10) -; R (5) and R (6) -CR (15) = CR (16) -CR (17) = N- or -CR (15) = CR (lß) -N = CR (17) -, 15 R (15), R (16) and R (17) independently of each other , hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF3, C2F5, C3F7, N3 , N02, -CONR (19) R (21), 20 -COOR (21), R (22) -C3H2s-Z- or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, -25 R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (2l) hydrogen, methyl, ethyl, phenyl or - CuH2u-NR (19) R (20); U2O3; 1R (20) hydrogen or alkyl having 1, 2 or 3 C atoms, the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from The group consisting of F, Cl, Br, I, CF3, methyl, 35 methoxy, sulfamoyl or methylsulfonyl, R (22) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -COOR ( 21), -CONR (19) R (21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, or C3F7 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; s zero, 1, 2, 3, 4, 5 or 6; Z - [S (0) cer ?? 1 or 2] -, -CO-, -S02-NR (11) -, -S02-0-, -O-, -NR (II) - or - [CO-NR (II)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, alkyl having 1, 2, 3 or 4 C atoms; R (8) hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; and their physiologically compatible salts. 4. Compounds of the formula I according to claims 1, 2 or 3, in which they mean: R (l) and R (2) independently of each other, hydrogen, CF3, C2F5, C3F7, alkyl with 1, 2, 3, 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (l) and R (2) in common, an alkylene chain with 2, 3, 4, 5 or 6 C atoms, - a CH2 group of the alkylene chain being able to be replaced by -O-, -CO -, -S-, -SO-, -S02- or -NR (10) -; R (10) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (3) R (12) -CaH2a-; R (12) hydrogen or cycloalkyl with 3, 4, 5, 6, 7 or 8 ft C atoms, CF3, C2F5 or C3F7; to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (4) R (14) -CrH2r; r 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; R (14) hydrogen, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methyl-piperazino, CF3, C2F5, C3F7, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, ft "methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; group CrH2r be replaced by -O-, -CH = CH-, -C = C-, -CO-, -CO-O-, -CO-NR (II) -, - [S0cer? / 1 O 21 - OR -NR (ll) -; R (ll) hydrogen or - (CaH2a) -R (10), a CH2 group of the CaH2a group being able to be replaced by -O-, -CH = CH-, 20 -C = C- , -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S02-, -NR (10) - OR -CON (10) -; R (10) hydrogen or alkyl with 1, 2 or 3 C atoms: R (5) and R (6) 25 -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, hydrogen, F, Cl, 'Br, I, alkyl with 1, 2, 3 or 4 C atoms , 30 cic loalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CN, CF3, C2F5, C3F7, N3, N02, -CONR (19) R (21), -COOR (21), R (22) - C3H2s-Z- or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; ft R (19) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (21) hydrogen, methyl, ethyl or phenyl, the phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl, • R (22) hydrogen; 10 s zero, 1, 2, 3, 4, 5 or 6; Z -CS (0) cßr? Fl or 2] -, -CO-, -S02-NR (11) -, ft -S02-0-, -O-, -NR (ll) --O - [CO-NR (ll)] -; R (7) hydrogen, hydroxy, alkoxy with 1, 2, 3 or 4 C atoms, alkyl having 1, 2, 3 or 4 C atoms; 15 R (8) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms, and their physiologically compatible salts. 5. Process for the preparation of compounds of the formula I according to one or more of claims 1 to 4, characterized in that a compound of the formula II is reacted in a manner known per se. where R (l), R (2), R (5), R (6), R (7) and R (8) have the indicated meanings and L means a nucleophilic labile group, especially F, Cl, Br, I, MeS02-0-, a p-toluenesulfonyloxy radical, or R (7) and L are in common an epoxide ring, with a sulfonamide or a salt thereof of the formula III wherein R (3) and R (4) have the indicated meanings and M represents hydrogen or preferably an atom of a metal, particularly preferably lithium, sodium or potassium; 5 or because b) a compound of the formula IV is reacted Wherein R (l), R (2), R (4), R (5), R (6), R (7) and R (8) have the indicated meaning, with a sulfonic acid derivative of the formula V wherein R (3) has the indicated meaning and means a nucleophilic leaving group, such as fluoro, bromo, 1-imidazolyl, but especially chloro, or because c) a compound is reacted in a manner known per se. of the formula VI wherein R (l), R (2), R (3), R (5), R (6), R (7), R (8) and M possess the indicated meanings, with an alkylating agent of the formula VII R (4) -L VII in the sense of an alkylation reaction, in which R (4) with the exception of hydrogen as well as L have the meanings indicated, - or because 10 d) in a compound of the formula I 20 in which R (l) through R (4), R (7) and R (8) have the indicated meanings, in at least one of the positions R (15), R (16), R (17) of the R (5) -R (6) ring system, an electrophilic substitution reaction is carried out, provided that 25 when this position means hydrogen and the remaining substituents R (l) to R (8) have the meanings indicated. 6. Compounds of the formula I according to one or more of claims 1 to 4 and their physiologically compatible salts for use as medicaments. 7. Pharmaceutical preparation, containing an effective amount of at least one compound of formula I according to one or more of claims 1 to 4, and / or a physiologically compatible salt thereof as active substance, 35 common with pharmaceutically acceptable vehicle and additive substances and optionally also one or more other pharmacological substances. ft 8. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament with blocking effect of K + channels for the therapy and prophylaxis of diseases mediated by K + channels. 9. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the therapy or prophylaxis of disorders of the heart rhythm, that can be solved by prolonging the action potential. ft 10. Use of a compound I according to claim for the preparation of a medicament for the treatment or prophylaxis of atrial fibrillation or atrial flutter. 11. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a 20 drug intended for the inhibition of gastric acid secretion. 12. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a 25 drug intended for the therapy or prophylaxis of ulcers of the stomach or intestinal region. 13. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a 30 drug intended for the therapy or prophylaxis of reflux esophagitis. 14. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the therapy or prophylaxis of diarrheal diseases. 15. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the therapy or prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias. 16. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the therapy or prophylaxis of reentry arrhythmias or for the avoidance of sudden cardiac death as a consequence of ventricular fibrillation. 17. Use of a compound of formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the therapy of heart failure, especially insufficiency Congestive Heart Failure. 18. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for blocking the potassium channel, which is opened by cyclic adenosine monophosphate (cAMP) . 19. Use of a compound of the formula I according to one or more of claims 1 to 4 and / or of a physiologically compatible salt thereof for the preparation of a medicament intended for the inhibition of stimulated secretion of gastric acids, for the therapy or prophylaxis of ulcers of the stomach or intestinal region, reflux esophagitis, diarrheal diseases, for the therapy or prophylaxis of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial flutter and reentry arrhythmias, or for the avoidance of sudden cardiac death as a consequence of ventricular fibrillation. 20. Medicaments, which contain an effective amount of a compound of the formula I according to claims 1 to

4.