MXPA98009370A - Condensed compounds with 5 members ring, substituted with sulfonamide, its use comomedicamentos, as well as pharmaceutical preparations that contains them - Google Patents

Abstract

Compounds of the formula I, with the meanings of the substituents indicated in the claims, are substances which are outstandingly effective for the preparation of medicaments intended for the prophylaxis and therapy of cardio-circulatory diseases, especially arrhythmias, for the treatment of colonic ulcers in the region gastro-intestinal or for the treatment of diarrheal diseases

Description

- i - Compounds condensed with 5-membered ring, substituted with sulfonamide, their use as medicaments, as well as pharmaceutical preparations containing them The invention relates to compounds of Formula I, where R (l), R (2), R (3), R (4), R (5), R (6), R (7), R (8), R (9) and X in that R (l), R (2), R (3), R (4), R (5), R (6) and B have the meanings indicated below, their preparation and their use, especially in medicines . The compounds influence the open potassium channel by cyclic adenosine monophosphate (cAMP) or the IRS-Y channel and are excellently 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 diseases of diarrhea. In the chemistry of medicinal products, intensive work was carried out in recent years on the class of 4-acylamino-chroman derivatives. The most prominent representative of this class is the cromakalim of Formula A (J. Med. Chem. 1986, 29, 2. 194). Homologous compounds, such as indane, were also synthesized and investigated beside it. Formula B, which is derived from it by narrowing of the pyran ring (J. Med. Chem. 1991, 34, 919).

In the case of cromakalim and other derivatives of 4-acylamino-chroman or related 1-acylamino-indane, these are compounds with relaxing effect on smooth muscle organs, so they are used to lower high blood pressure, as a consequence of the relaxation of the 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, for example of smooth muscle cells, and there lead to an opening of certain K + channels sensitive to ATP. The increase of the negative electrical charge in the cell (hyperpolarization), induced by the exit of K + ions, counteracts through secondary mechanisms the increase of the intracellular concentration of Ca2 + and consequently to a cellular activation, which leads p. ex. to a contraction of the muscles. Of these acylamines, the compounds of Formula I according to the invention are structurally differentiated, inter alia, by the replacement of the acylamino group with a sulfonylamino function. While cromakalim (Formula A) and analogous acylamine compounds (eg compound B) act as catalysts for ATP-sensitive K + channels, the compounds of Formula I according to the invention with the sulfonylaminic structure do not, however, exhibit any opener effect on this K + channel (ATP), but surprisingly they have an intense and specific blocking (closing) effect on a K + channel, which has been opened by cyclic adenosine monophosphate (cAMP) and which differs fundamentally of the mentioned channel of K * (ATP). More recent research has shown that this K + channel (cA P) identified in tissue of the large intestine is very similar, and possibly even identical, to the channel of IKs identified in the cardiac muscle (myocardium). In fact, a strong blocking effect on the channel of IKs in guinea pig cardiomyocytes as well as on the IsK channel expressed in Xe opus oocytes could be demonstrated for the compounds of Formula I according to the invention. As a result of this blocking of the K + channel (cAMP) or the IK channel, the compounds according to the invention develop pharmacological effects of high therapeutic utility in a living organism. In addition to the above-mentioned chromakalim or acylamino-chroman derivatives, there are also described in the literature compounds with 4-sulfonylamino-chroman structure, which, however, manifestly differ both in the structure and in the biological effect, of the compounds of the Formula I according to the invention. Thus, in EP-A-315,009 there are described chroman derivatives with 4-phenylsulfonylamino structure, which are distinguished by antithrombotic and antiallergic properties. European Patent Documents EP-A-389,861 and Japanese Patent JP 01294677 describe 3-hydroxy-chroman or chromene derivatives having a 4-cyclic sulfonylamino group (eg Compound C), which must act as antihypertensive agents through activation of the K + channel (ATP). EP-A-370,901 discloses derivatives of hydroxy-chroman or chromene with a 4-sulfonylamino group, the remaining valence of the N atom being a hydrogen atom, which have effects on the central nervous system (CNS) . Other 4-sulfonylamino-chroman derivatives are described in Bioorg. Med. Chem. Lett. 4 (1994), 769-773: "N-sulfonamides of benzopyran -related potassium channel openers: conversion of glyburide insensi tive smooth muscle relaxants to potent muscle contrac-tors" as well as in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly .activating lsK channels by chromanols ..." and Pflügers Arch. - Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-mediated Cl-secretion in rabbit colon, acting by the reduction of cAMP -activated K + conductance".

The present invention relates to compounds of Formula I, in which they mean: R (l) and R (2) independently of each other, hydrogen, CF3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms: or R (2) and R (9) in common a link; or R (2) -OR (10a), when X means -CR (22) R (23) -; R (10a) hydrogen, acetyl or alkyl having 1, 2 or 3 carbon atoms; R (3) R (10b) -CnH2n-NR (ll) - or R (10b) -CnH2n-, with a CH2 group in the CnH2n groups being replaced by -0-, -CO-, -S-, -SO -, -S02- or -NR (12a) -, - R (12a) hydrogen, methyl or ethyl; R (10b) methyl, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (ll) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (10b) and R (ll) in common, a link, as long as n is greater than 2; or R (3) in common with R (4) 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-, -CO -, -S-, -SO-, -S02- or -NR (12a) -; R (12a) hydrogen, methyl or ethyl, -R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-, -CH = CH-, - C = C-, -CO -, -C0-0-, -O-CO-, -S-, -SO-, -S02-, -NR (14) - or -C0NR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CyH2y-OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl, - and 2 or 3; R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -NR (15) R (16), -CONR (15) R (16), - 0R (17), -COOR (17), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms; wherein the phenyl and the heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3) - or -N (benzyl)) -; R (17) hydrogen, alkyl having 1, 2 or 3 carbon atoms; -CzH2z0R (12c); R (12c) hydrogen, methyl or ethyl; z 2 or 3; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (5), R (6), R (7) and R (8), independently of each other, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -CN, -CF3, -C2F5, -C3F7, -N3, -N02, -Y-C3H2s-R (18), phenyl, thienyl, furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl, thienyl, furyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -so2-, -0-S02-, -SO2NR (10c) - or -CONR (lOc) ) -, making the union with the fundamental framework in each case through the atom located on the left; R (10c) hydrogen or alkyl having 1, 2 or 3 C atoms; s zero, 1, 2, 3, 4, 5 or 6; R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -0R (21), -C0OR (21), -NR (15a) R ( 16a), -CONR (15a) R (16a), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle containing N be unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15a) and R (16a) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15a) and R (16a) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3T- or - (benzyl) -; R (21) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond; X-CR (22) R (23) -, -0-, -NR (24) -, -S-, -SO-, -S02-; R (22) and R (23) independently of one another, hydrogen, CF 3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (24) hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or phenyl, which is unsubstituted or substituted by 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as its physiologically compatible salts.

Preferred are compounds of Formula I, in which they mean: R (1) hydrogen; R (2) hydrogen or -OR (10a); R (10a) hydrogen, acetyl or alkyl having 1, 2 or 3 carbon atoms; or R (2) and R (9) in common, a bond, -R (3) R (10b) -CnH2n-NR (ll) - or R (10b) -CnH2n-, with a CH2 group in the CnH groups -, n be replaced by -0-, -CO-, -S-, -SO-, -S02 - or -NR (12a) -; R (12a) hydrogen, methyl or ethyl; R (10b) methyl, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (ll) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (10b) and R (ll) in common, a link, as long as n is greater than 2; or R (3) in common with R (4) 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 -0-, -CO -, -S-, -SO-, -S02- OR -NR (12a) -; R (12a) hydrogen, methyl or ethyl, -R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-, -CH = CH-, -C = C-, -CO -, -C0-0-, -O-CO-, -S-, -SO-, -S02-, -NR (14) - or -C0NR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 C atoms; -CyH2y-OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl, - and 2 or 3; R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -NR (15) R (16), -CONR (15) R (16), - OR (17), -COOR (17), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl being and the heterocycle containing N without substituting or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which uri "CH2 group can be replaced by -O-, -S-, -NH-, -N (CH3 ) - or -N (benzyl) -; R (17) hydrogen, alkyl having 1, 2 or 3 carbon atoms, - CzH2zOR (12c), R (12c) hydrogen, methyl or ethyl, - z 2 or 3, - r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (5), R (6), R (7) and R (8) independently of each other, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -CN, -CF3, -C2F5, -C3F7, -N3, -N02, -Y-C3H2s-R (18), phenyl, thienyl, furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl, thienyl, furyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents , selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulphamoyl, methylsulfonyl and methylsulfonylamino; Y -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -so2-, -0-S02-, -S02NR (10c) - or -CONR (lOc) ) -, making the union with the fundamental framework in each case through the atom located on the left; R (10c) hydrogen or alkyl having 1, 2 or 3 C atoms; s zero, 1, 2, 3, 4, 5 or 6; R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -OR (21), -C00R (21), -NR (15a) R ( 16a), -CONR (15a) R (16a), phenyl, or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle being contains N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15a) and R (16a) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15a) and R (16a) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -O-, -S-, -NH-, -N (CH3 > - or -N (benzyl) -, - R (21) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, - X -CR ( 22) R (23) -; R (22) and R (23) independently of one another, hydrogen, CF 3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, as well as their physiologically compatible salts.

Especially preferred are compounds of Formula I, in which they mean: R (1) hydrogen; R (2) hydrogen or -? R (10a); R (10a) hydrogen, acetyl or alkyl with 1, 2 or 3 C atoms, -or R (2) and R (9) in common, a bond, -R (3) R (10b) -CnH2n-, R (10b) methyl, cycloalkyl with 3, 4, 5 or 6 C atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4 or 5; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being replaced by -0-, -CO-, -C0-0-, -O-CO-, -NR (14) - or -CONR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CyH2y-OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl; and 2 or 3; R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5 or 6 C atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17) , -COOR (17), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl being and the heterocycle containing N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, -R (15) and R ( 16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3 ) - or -N (benzyl) -; R (17) hydrogen or alkyl having 1, 2 or 3 carbon atoms, -r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (5), R (6), R (7) and R (8) independently of one another, hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3 , 4, 5 or 6 C atoms, -CN, -CF3. -C2F5, -C3F7, -N02, -Y-C3H2s-R (18), phenyl, thienyl, furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms C, the phenyl, thienyl, furyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, - Y -0-, -CO-, -C0-0-, -O-CO-, -S-, -SO-, -S02-, s zero, , 2, 3, 4, 5 or 6; R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5 or 6 C atoms; -0R (21), -C00R (21), -NR (15a) R (l6a), -CONR (15a) R (lßa), phenyl or a heterocycle containing NT with i, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, NH2, OH , methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15a) and R (16a) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15a) and R (16a) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -O-, -S-, -NH-, -N (CH3) - or -N (benzyl) -; R (21) alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, - X -CR (22) R (23) -; R (22) and R (23) independently of one another, hydrogen, CF-,, alkyl having 1, 2 or 3 C atoms; as well as its physiologically compatible salts.

Especially preferred are compounds of Formula I, in which they mean: R (1) hydrogen; R (2) hydrogen or -OR (10a), - R (10a) hydrogen or methyl, -o R (2) and R (9) in common, a bond, -R (3) R (10b) -CnH2n- , R (10b) methyl; n zero, 1 or 2; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being replaced by -0-, -CO-, -C0-0- or -CONR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CyH2y-OR (12b); R (12b) hydrogen, methyl or ethyl; and 2 or 3; R (13) CH3, CF3 or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents , selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; r zero, 1, 2, 3, 4, 5, 6, 7 or 8, -R (5), R (7) and R (8) hydrogen; R (6) hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5 or 6 C atoms, -CN, -CF3, -C2F5, - C3F7, -N02, -Y-C3H2s-R (18), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle being containing N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy: Y -0-; S 1, 2, 3, 4, 5 or 6; R (18) hydrogen, CF3, -0R (21), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenium and the heterocycle being contains N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; R (21) alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, - X -CR (22) R (23) -; R (22) and R (23) independently of one another, CF3 or methyl, - as well as their physiologically compatible salts.

The compounds of Formula I, in which they mean: R (1) hydrogen, are particularly preferred; R (2) hydrogen; R (3) methyl or ethyl; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being able to be replaced by -O-, - R (13) CH3 or CF3; r zero, 1, 2, 3, 4, 5 or 6; R (5), R (7) and R (8) hydrogen, -R (6) F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, -CN, -CF3, -N02 , -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; And -0-; S 1, 2, 3, 4, 5 0 6; R (18) hydrogen, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy, -R (9) hydrogen; X-CR (22) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts.

Also particularly preferred are compounds of Formula I, in which they mean: R (l) hydrogen; R (2) OH; R (3) methyl or ethyl; R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-; R (13) CH 3 or CF 3; r zero, 1, 2, 3, 4, 5 or 6; R (5), R (7) and R (8) hydrogen, -R (6) F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, -CN, -CF3, -N02 , -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy, - Y - O-; S 1, 2, 3, 4, 5 0 6; R (18) hydrogen, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; R (9) hydrogen; X-CR (22) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts.

The compounds of Formula I, in which they mean: R (l) hydrogen, are also particularly preferred; R (2) in common with R (9), a bond; R (3) methyl or ethyl, -R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-, - R (13) CH3 or CF3; r zero, 1, 2, 3, 4, 5 0 6; R (5), R (7) and R (8) hydrogen, - R (6) F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, -CN, -CF3 or -N02 , -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; And -0-; s 1, 2, 3, 4, 5 or 6; R (18) hydrogen, CF3 or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; X-CR (22) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts. ( The alkyl radicals and alkylene radicals may be linear or branched. This also applies to the alkylene radicals of the formulas CrH2r, CnH2n and CsH2s. The alkyl radicals and alkylene radicals may also be linear or branched, when substituted or contained in other radicals, e.g. ex. in an alkoxy radical or in an alkylmercapto radical or in a fluorinated alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere. -butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethyl-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl . The bivalent radicals derived from these radicals, p. eg methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butylene, 1,5 -pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc., are examples of alkylene radicals. As heterocycles containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, aromatic systems 1- are especially valid, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1, 2, 3-triazole-1-, -4- or - 5-yl, 1, 2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl , 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, 4-oxadiazol-3-y-5-yl, 1, 3, 4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2-yl or -5-yl, 1,2,4-thiadiazole-3- or -5 -yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl , 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2 -, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 3-, 5-, 6- , 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Particularly preferred are heterocycles containing N-pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. Thienyl represents both 2- and 3-thienyl. Furilo represents 2- and 3 -furyl. The monosubstituted phenyl radicals can be substituted in positions 2, 3 or 4, disubstituted in positions 2,3, 2,4, 2,5, 2,6, 3,4 or 3, 5. "The corresponding is opportunely valid analogously also for heterocycles containing N or for the thiophene radical.In the case of disubstitution of a radical, the substituents may be the same or different.If R (2) and R (9) mean a bond in common, presents a fundamental lattice of 3H-indene, provided that X represents CR (22) R (23), or an indole, benzofuran or benzothiophene, as long as X represents NR (24), OR • or S. If R (10b) and R (ll) mean in common a bond, the group R (10) -CnH2n-NR (11) - preferably represents a nitrogen-containing heterocycle linked through a nitrogen atom. When R (10) and R (ll) mean in common a bond, and the group R (10) -CnH2n-NR (11) - represents a nitrogen-heterocycle linked through a nitrogen atom, this nitrogenous heterocycle is preferably a 4-membered ring or a ring or ring larger than a 4-membered ring, e.g. ex. a 5-membered ring, 6-membered ring or 7-membered ring. If the compounds of the formula I contain one or more basic or acidic groups or one or more basic heterocycles, the corresponding physiologically or toxicologically compatible salts, especially the pharmaceutically usable salts, belong to the invention. Thus, the compounds of Formula I, which carry acidic groups, e.g. ex. one or more COOH groups, for example in the form of alkali metal salts, preferably sodium or potassium salts, or in the form of alkaline earth metal salts, e.g. e. salts of calcium or magnesium, or in the form of ammonium salts, p. ex. in the form of salts with ammonia or organic amines or amino acids. The compounds of Formula I, which carry one or more basic groups, that is to say protonatable, or which contain one or more basic heterocyclic rings, can also be used in the form of their salts by the addition of acids physiologically compatible with inorganic acids or organic compounds, for example in the form of hydrochlorides, phosphates, sulphates, methanesulfonates, acetates, lactates, maleates, fumarates, maleates, gluconates, etc. If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule, together with the salt forms that are also exposed, internal salts, the so-called betaines, belong to the invention. The salts can be obtained from the compounds of Formula I according to customary methods, for example by meeting with an acid or a base in a solvent or dispersant, or also by exchanging anions from other salts. . The compounds of Formula I can be present in stereoisomeric forms in the case of having a corresponding substitution. If the compounds of Formula I contain one or more centers of asymmetry, these may have, independently of one another, the S configuration or the R configuration. All possible stereoisomers, e.g. ex. enantiomers or diastereoisomers, and mixtures of two or more stereoisomeric forms, e.g. ex. enantiomers and / or diastereomers, in any ratios. The enantiomers, p. ex. , therefore, belong to the invention in pure form as regards the enantiomers, in the form of both levorotatory and dextrorotatory antipodes, and also in the form of mixtures of both enantiomers in different ratios or in the form of racemates. In the case of a cis / trans isomerism, both the cis form and also the trans form and mixtures of these forms belong to the invention. 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 tautomeric forms of the compounds of Formula I. The compounds of Formula I can be prepared by different chemical methods. Thus, for example, a compound of Formula I is obtained, a) by reacting in a manner known per se with a compound of Formula II, R (8) wherein R (l), R (2), R (5), R (6), R (7), R (8) and X have the meanings indicated above and L means a nucleophilic leaving group, especially Cl, Br, I, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy, with a sulfonamide or a salt thereof of Formula III, wherein R (3) and R (4) have the meanings indicated above and M represents hydrogen or preferably one equivalent of a metal, particularly preferably lithium, sodium or potassium; b) reacting a compound of Formula IV wherein R (l), R (2), R (4), R (5), R (6), R (7), R (8), R (9) and X have the meanings indicated above, with a sulfonic acid derivative of Formula V or V W R (3) in which R (3) has the meanings indicated above and means a nucleophilic leaving group, such as p. ex. fluoro, bromo, 1-imidazolyl, but especially chloro, or c) reacting a compound of Formula VI R (8) where R (l), R (2), R (3), R (5), R (6), R (7), R (8), R (9), X and M have the meanings before indicated, in a manner known per se in the sense of an alkylation reaction, with an alkylating agent of Formula VII, R (4) -L Vli in which R (4) and L have the meanings indicated above, - od) in a compound of Formula I, wherein R (l) through R (9) and X have the meanings indicated above, carried out in at least one of the positions R (5), R (6), R (7) and R (8) an electrophilic substitution reaction, provided that this position means hydrogen, - oe) by reacting a compound of Formula VIII wherein R (l), R (2), R (3), R (4), R (5), R (7), R (8), R (9) and X have the meanings indicated above, with a compound of the formula R (18) -C3H2s-L, wherein R (18), s and L have the meanings indicated above, in the sense of an alkylation reaction, - of) by reacting a compound of the Formula IX, wherein R (5), R (6), R (7), R (8), R (22) and R (23) possess the meanings indicated above, -with a sulfonamide of Formula III, in which R (3) and R (4) have the meanings indicated above and M represents hydrogen or an equivalent of a metal, preferably lithium, sodium or potassium, or M advantageously also represents a trialkyl silyl radical, e.g. ex. a trimethylsilyl radical, to form a hydroxy indane of Formula la; g) by reacting in a manner known per se a compound of the formula la with an alkylating agent of the formula R (10a) -L or with an acylating agent of the formula CH3C0L or with an anhydride of the formula (CH3C0) 20, in which R (l? A) and L possess the meanings indicated above, with the exception of hydrogen, in the sense of an alkylation or acylation reaction to form a compound of Formula Ib, in which R (3) , R (4), R (5), R (6), R (7), R (8), R (l? A), R (22) and R (23) have the meanings indicated above, Ib h) transforming a compound of the Formula la, wherein R (3), R (4), R (5), R (6), R (7), R (8), R (22) and R (23) have the meanings indicated above, in the sense of an elimination reaction to form a compound of Formula LE, wherein R (3), R (4), R (5), R (6), R (7), R (8), R ( 22) and R (23) have the meanings indicated above.

Process mode a) corresponds to the nucleophilic substitution of a leaving group in a reactive bicyclic compound of Formula II by a sulfonamide or a salt thereof of Formula III. Because of the higher nucleophilicity and the higher reactivity of a sulfonamide present in the form of a salt, in the case of using a free sulfonamide (Formula III, M = H) it is preferred to generate from it first a sulfonamide salt (Formula III, = cation of a metal) by the action of a base. If a free sulfonamide (Formula III, M = H) is used, the deprotonation of the sulfonamide to form the salt can be carried out in itself. Preferably, the bases are used which themselves are not alkylated or only poorly alkylated, such as p. ex. sodium carbonate, potassium carbonate, sterically hindered amines, p. ex. dicyclohexylamine, N, N-dicyclohexyl-ethylamine or other strong nitrogenous bases with small nucleophilicity, for example DBU (1,8-diaza-bicyclo [5.4.0] undec-7-ene) or N, ', N' '' - triisopropyl-guanidine. 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, such as for example Ca (0H) 2. Preferably, it is worked in a solvent, particularly preferably in polar organic solvents such as p. ex. dimethyl-formamide (DMF), dimethyl-acetamide (DMA), dimethyl-sulfoxide (DMSO), tetramethyl-urea (TMU), hexamethyl-triamide-phosphoric acid (HMPT), • tetrahydrofuran (THF), dimethoxy-ethane (DME) or other ethers, or for example also in a hydrocarbon such as toluene or in a halogenated hydrocarbon such as chloroform or methylene chloride. However, it is also possible to work in polar protic solvents, such as p. ex. in water, methanol, ethanol or isopropanol. The reaction is preferably carried out in a temperature range of -10 to +140 ° C, particularly preferably in the range of 20 to 100 ° C. In a favorable manner, the procedure mode a) can also be carried out under the conditions of a phase transfer catalysis. The compounds of the formula II are obtained according to methods known from the literature, for example from the corresponding alcohols (Formula II, L = -OH) by the action of a hydrogen halide HL (L = Cl, Br, I ) or by the action of an inorganic acid halide (P0C13, PC13, PC15, S0C12, SOBr2) or by radical halogenation of the corresponding derivatives of Formula II, in which L means hydrogen, with radical-activatable halogenation agents such as N-bromo-succinimide (NBS) or S02C12 (sulfuryl chloride) in the presence of a radical chain initiator, such as energy-rich light of the visible or ultraviolet wave region, or by use of a radical chemical initiator such as azo-di-isobutylsitrile.

Process mode b) describes the known and frequently applied reaction of a reactive sulfonyl compound of formula V, especially a chlorosulfonyl compound (W = Cl), with an amino derivative of formula IV to form the corresponding sulfonamide derivative of the formula I. The reaction is preferably carried out using a polar solvent, preferably in the presence of a base, which can itself be used advantageously as a solvent, e.g. ex. in the case of using 'triethylamine, especially pyridine and its homologs. The solvents also used are for example 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 from 0 to 160 ° C, preferably from 20 to 100 ° C. The amines of Formula IV are obtained in a manner known from the literature, preferably from the corresponding carbonyl compounds of Formula XX, wherein R (l), R (2), R (5), R (6), R (7), R (8) and X have the meanings indicated above and A means oxygen, either with ammonia or with an amine of Formula XXI, R (4) -NH2 XXI wherein R (4) has the indicated meanings, under reducing conditions or under reducing catalytic conditions, preferably at elevated temperature and in an autoclave. In such case they are formed primarily, by a condensation reaction of the ketones of Formula XX (A = oxygen) and of the amines of Formula XXI, in itself your Schiff bases of Formula XX, wherein A represents R (4) -N =, which can be transformed immediately, ie without previous isolation, by reduction in the amines of Formula IV. However, Schiff bases can also be prepared according to methods known from the literature (Formula XX, A represents R (4) -N =) which are formed in an intermediate manner in the condensation reaction from the compounds of Formulas XX and XXI, and can be isolated first, then transformed into a step performed separately with an appropriate reducing agent, such as p. ex. NaBH4, ÍA1H4, NaBH3CN, or by, catalytic hydrogenation in the presence of p. ex. Raney nickel or a noble metal, such as p. ex. palladium, in the compounds of Formula IV. The compounds of Formula IV, in which R (4) represents hydrogen, can advantageously be obtained in a manner known from the literature also by reduction of oximes or oxime-ethers (Formula XX, A represents = N-OR, R = H or alkyl) or hydrazones (Formula XX, A represents = N-NR2, R is eg = H or alkyl), p. ex. by using a complex metal hydride or by catalytic hydrogenation. The oximes and hydrazones necessary for this are preferably prepared in a manner known per se from the ketones of Formula XX (A = oxygen) with hydrazine or one of its derivatives, or for example with hydroxylamine hydrochloride under the conditions of separation of water. In a particularly advantageous manner, the compounds of the formula IV, in which R (4) represents hydrogen, can also be obtained by amination of ketones of the formula XX (A = oxygen) with an appropriate ammonium compound, e.g. ex. ammonium acetate, in the presence of an appropriate reducing agent, such as p. ex. NaCNBH3 (J. Am. Chem. Soc. 93, 1971, 2. 897). The ketones of Formula XX (A = oxygen) are either known or can be prepared analogously to the methods described. Some suitable ketones of Formula XX, wherein X means CR (22) R (23) are described p. ex. in J. Org. Chem. 19, 1954, 305 or in Org. Prep. Proc. Int. 10, 1978, 123. Ketones of Formula XX, wherein X means oxygen, are described p. ex. in J. Org. Chem. 26, 1961, 4. 758 or in Monatsh. Chem. 125, 1994, 971. Alternatively, the amino derivatives of Formula IV can also be obtained in a manner known per se from the literature by reacting the reactive compounds of Formula II with R (l), R (2), R (5), R ( 6), R (7), R (8), X and L with the indicated meanings, either with ammonia or with an amine of Formula XXI, having R (4) the indicated meaning.

Process mode c) represents the alkylation reaction known per se of a sulfonamide or one of its salts VI with an alkylating agent of formula VII. Corresponding to the analogy of reactions with procedure mode a), the reaction conditions already described in detail during procedure mode a) are valid for process mode c). The preparation of the sulfonamide derivatives VI (with M = H) and that of their precursor products were already described in the case of mode b) of the process, R (4) then meaning hydrogen each time. The preparation of the alkylating agents VII is carried out according to analogous prescriptions of the literature or as described in the case of process mode a), preferably from the corresponding hydroxyl compounds (Formula VII with L equal to OH).

Process mode d) describes the further chemical conversion of compounds of the formula I according to the invention to other compounds of the formula I by electrophilic substitution reactions at one or more of the positions designated by R (5) to R (8) , which in each case means hydrogen. Preferred substitution reactions are 1. aromatic nitration for the introduction of one or more nitro groups, which can be reduced in subsequent reactions, partially or in whole, to form amino groups. The amino groups can in turn be converted into subsequent reactions in other groups, for example in a Sandmeyer reaction, e.g. ex. for the introduction of cyano groups; 2. aromatic halogenation especially for the introduction of chlorine, bromine or iodine; 3. chlorosulfonation, p. ex. by the action of chlorosulphonic acid, for the introduction of a chlorosulfonyl group, which in subsequent reactions can be transformed into other groups, p. ex. in a sulfonamido group; 4. the Friedel-Crafts acylation reaction for the introduction of an acyl radical or a sulphonyl radical by the action of the corresponding acid chlorides in the presence of a Lewis acid as a Friedel-Crafts catalyst, preferably in the presence of sodium chloride. anhydrous aluminum Process mode e) describes the alkylation of a phenol of Formula VIII with an alkylating agent of the formula R (18) -C3H2s-L. For this, the phenol is first transformed by the action of an appropriate base, such as p. ex. sodium hydride, in a phenolate salt, which is then reacted with the alkylating agent in an appropriate polar solvent such as p. ex. dimethylformamide or dimethyl acetamide, at temperatures between 20 and 150 ° C. The deprotonation of the alcohol to form the salt can also be carried out in itself, then bases are preferably employed, which by themselves are not alkylated, such as p. ex. Potassium carbonate. As other suitable bases and other suitable solvents, those already mentioned during process mode a) can also be used. The phenols of Formula VIII are obtained according to the methods described above in items a) to c) or described below in paragraphs f) to h), however, meaning R (6) in each case OH or OR (R = appropriate protecting group, eg benzyl) and, in the latter case, a subsequent separation of the protecting group.

Process mode f) corresponds to the nucleophilic opening of an epoxide of Formula IX by a sulfonamide or one of its salts of Formula III. In the case of using a free sulfonamide (Formula III, M = H) it is preferred to produce from it first, by the action of a base, a sulfonamide salt (Formula III, M = cation of a metal), and Do the de-protonation of the sulfonamide to form the salt. For this purpose, the aforementioned bases can be used on the occasion of procedure mode a). The base can be used in stoichiometric quantity or also catalytically. The use of free sulfonamide in the presence of a small amount has proved to be particularly advantageous., p. ex. 20%, of the corresponding sodium salt of sulfonamide, which can be obtained from the sulfonamide p. ex. by addition of 0.2 molar equivalents of sodium hydride. The reaction is preferably carried out in a solvent, particularly preferably in polar organic solvents such as p. ex. dimethylformamide (DMF), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), tetramethyl urea (TMU), hexamethyltriamide phosphoric acid (HMPT), tetrahydrofuran (THF) or dimethoxyethane (DME). The reaction is preferably carried out in a temperature range of -10 to +140 ° C, especially preferably in the range of 20 to 100 ° C. Another preferred mode of procedure for carrying out this reaction involves the use of sulfonamide derivatives of Formula III, in which M represents a trialkyl silyl radical, e.g. ex. a trimethyl-silyl radical. In this case it is advantageous to carry out the reaction in the presence of a p-fluoride. ex. tetrabutylammonium fluoride. The epoxides of Formula IX are obtained according to methods known from the literature from the corresponding olefins of Formula XXII, wherein R (5), R (6), R (7), R (8), R (22) and R (23) have the meanings indicated above, p. ex. by the action of an appropriate inorganic or organic peroxide, such as for example H202 or m-chloroperbenzoic acid, or by base-catalyzed cyclization of the corresponding bromohydrin, which can be obtained from XXII p. ex. by reaction with N-bromo-succinimide and water. The epoxides of Formula IX can be obtained from olefins of Formula XXII also in optically pure form, by oxidation in the presence of the Jacobsen chiral catalyst, as described p. ex. in Tetrahedron Letters 32, 1991, 5. 055. The olefins of Formula XXII can be obtained from the ketones of Formula XX (A = O, X = CR (22) R (23)) by reduction of the carbonyl group to form an OH function, p. ex. with sodium borohydride, and subsequent acid catalyzed removal, p. ex. by heating with p-toluenesulfonic acid in toluene.

Process mode g) describes the conversion of compounds of formula la, according to the invention, into other compounds of formula Ib, according to the invention, by alkylation or acylation of the 2-hydroxy group. For alkylation, the alcohol is transformed first, by the action of an appropriate base, such as p. ex. sodium hydride, in an alcoholate salt, which is then reacted in an appropriate polar solvent, such as p. ex. dimethylformamide, at temperatures - comprised between 20 and 150 * C with the alkylating agent of Formula R (10a) -L. The deprotonation of the alcohol to form the salt can also be carried out in itself, then bases are preferably employed, which by themselves are not alkylated, such as p. ex. Potassium carbonate. As other bases and other suitable solvents, the aforementioned ones can be used during process mode a). The acetylation of the compounds of Formula Ia is preferably carried out by reaction with acetic anhydride in an appropriate polar solvent, such as pyridine or dimethyl formamide and optionally by addition of acylation catalyst such as p. ex. dimethylaminopyridine.

Process mode h) describes the transformation of a 2-hydroxy-indane of the Formula Ia into an indene of the Formula I by elimination. For this, the 2-hydroxy-indane can either be subjected directly to a water separation in the presence of an acid or a base, or first activation of the hydroxy group can be effected, e.g. ex. by acetylation with acetic anhydride (see method g) of the process) or by mesylation with methanesulfonic acid chloride, after which a base-catalyzed elimination can be carried out, e.g. ex. by heating with DBU (1,8-diazabicyclo [5.4.0] undec-7-ene).

In all modes of procedure it may be appropriate to temporarily protect functional groups in the molecule in the case of certain reaction steps. Such protective group techniques are common to one skilled in the art. The choice of a protective group for the groups that come into consideration, and the procedures for their introduction and separation, are described in the bibliography and may eventually be adapted to each individual case without difficulties. It has already been said that the compounds of Formula I surprisingly have a strong and specific blocking effect (closer) on a K + channel, which has been opened by cyclic adenosine monophosphate (cAMP) and which differs fundamentally from the K + channel (ATP ) well known, and that this K + channel (cAMP) identified in tissue of the large intestine is very similar, possibly even identical, with the IK channel identified in the cardiac muscle. For the compounds according to the invention, a strong blocking effect on the IK channel could be demonstrated in guinea pig cardiomyocytes as well as in the IsK channel expressed in Xenopus oocytes. As a consequence of this blocking of the K + channel (cAMP) or the IKs channel, the compounds according to the invention develop pharmacological effects of high therapeutic utility in the living organism and are outstandingly suitable as active medicinal substances for the therapy and prophylaxis of different symptomatological conditions. Thus, the compounds of Formula I according to the invention are distinguished as a new class of active substances of potent inhibitors of stimulated secretion of gastric acids. The compounds of 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. These are also adapted, due to their strong inhibitory effect on the secretion of gastric juices, as excellent therapeutic agents for the therapy and prophylaxis of reflux esophagitis. The compounds of Formula I according to the invention are furthermore distinguished by an antidiarrheal effect and are therefore suitable as active medicinal substances for the therapy and prophylaxis of diarrheal diseases. In addition, the compounds of 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 prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, especially heart rhythm disorders, which can be suppressed by prolonging the action potential. especially for the therapy and prophylaxis of atrial fibrillation (atrial fibrillation) and for atrial flutter (atrial flutter) as well as for the therapy and prophylaxis of reentry arrhythmias and for the inhibition and avoidance of sudden cardiac death as a consequence of a ventricular fibrillation.

Even when numerous substances with an antiarrhythmic effect are already on the market, there is no compound that is really satisfactory in terms of activity, the range of applications and the profile of side effects, so there is still a need for the development of improved antiarrhythmic agents. The effect of numerous known antiarrhythmic agents of the so-called class III is based on an increase in the myocardial refractory time by prolonging the duration of the action potential. This is essentially determined by the magnitude of the repolarizing K + currents, which flow out of the cells through different K + channels. A particularly important importance is attributed in this case to the so-called delayed rectifier = "delayed recti -fier" I ?, of which there are two subtypes, one rapidly activated 1- ^ and one slowly activated IKs. Most known class III antiarrhythmic agents block predominantly or exclusively the IKr (eg dofetilide, d-sotalol). However, it has been shown that these compounds, in the case of small or normal heart rates, present a high proarrhythmic risk, with arrhythmias being observed, which are designated as "Torsades de pointes" (DM Roden; "Current Status of Class III"). An-tiarrhyth ic Drug Therapy "; Am. J. Cardiol. 72 (1993), 44B-49B). In the case of higher cardiac frequencies or a stimulation of the ß-receptors, on the contrary, the prolongation effect of the action potential of the IKr blockers is clearly reduced, which is attributed to the fact that under these conditions the IKs contribute more strongly to repolarization. For these reasons, the substances according to the invention, which act as blocking agents of IKs, have essential advantages compared to the known IKr blocking agents. In the meantime, it was also described that there is a correlation between the inhibitory effect of the IK channel and the repression of life-threatening cardiac arrhythmias, such as are caused, for example, by hyper-stimulation -adrenergic (eg TJ Colatsky, CH Follmer and CF Starmer, "Channel Specifici ty in Antiarrhythmic Drug Action; Mechanism of potassiu channel block and i ts role in suppressing and aggravating cardiac arrhythmias" Circulation 82 (1990), 2,235-2,242, A. Busch, K. Malloy, WJ Groh, MD Varnu, JP Adelman and J. Mayllie; "The novel class III anti-arrythmics NE-10064 and NE-10133 inhibit IsK channels in Xenopus oocytes and IKs in guinea pig cardiac yocytes"; Biochem. 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 that favor contraction (positive inotropic), e.g. ex. phosphorus-diesterase inhibitors. Despite the therapeutically useful advantages, which can be achieved by blocking the IKs, only very few compounds that inhibit this subtype of the "delayed rectifier" have been described so far. 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 blockers of the IKs is claimed. Other blockers of the IKs are described in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating IsK channels by chromanols ..." and Pflügers Arch A 'Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-ediated Cl -secretion in rabbi t colon, acting by the reduction of cAMP -activated K + conductance".

The compounds of the formula I according to the invention and their physiologically compatible salts can therefore be used in animals, preferably in mammalian animals, and especially in humans, as medicaments by themselves, in mixtures with one another or in the form of pharmaceutical preparations. The present invention also relates to compounds of Formula I and their physiologically compatible salts for their application as medicaments, their use in therapy and the prophylaxis of the aforementioned symptoms, as well as their use for the preparation of medicaments therefor and for medications with a blocking effect of K + channels. In addition, the present invention provides pharmaceutical preparations which, as active constituents, contain an effective dose of at least one compound of Formula I and / or a physiologically compatible salt thereof, together with conventional pharmaceutically acceptable 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 purpose, the compounds of Formula I and / or their physiologically compatible salts in common with one or more vehicle materials and / or galenic adjuvants, solid or liquid and, when desired, a combination with other active medicinal substances, can be used. lead to an appropriate form of presentation or dosage form, which can then be used as a medicine in human medicine or in veterinary medicine. The medicaments, which contain compounds of the formula I according to the invention and / or their physiologically compatible salts, can be applied by the oral, parenteral routes, e.g. ex. intravenous, rectal, inhalation or topical, being the preferred application dependent on each individual case, p. ex. of the respective table of presentation of the disease to be treated. To establish which adjuvant materials are suitable for the desired drug formulation, it is usual for an expert in the field by virtue of his knowledge of the specialty. In addition to solvents, gel-forming agents, suppository bases, coadjuvant materials for tablets and other vehicles of active substances, antioxidants, dispersing agents, emulsifiers, antifoams, flavor correctors, preservatives, solubilizers and agents can be used. a deposit effect (delayed release), buffer substances or dyes. The compounds of Formula I can be combined, in order to achieve an advantageous therapeutic effect, also with other active medicinal substances. Thus, in the treatment of cardio-circulatory diseases, combinations with active substances on the heart and circulation are possible. As such combination partners, 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. dofetilide, or in addition hypotensive substances, such as inhibitors of ACE (angiotensin-converting enzyme) (eg enalapril, captopril, ramipril), angiotensin antagonists, K + channel activators, as well as alpha- and beta-receptor blockers, but also compounds that act sympathomimetic and adrenergic, as well as inhibitors of the exchange between Na + and H +, calcium channel antagonists, phospho-diesterase inhibitors and other substances with positive inotropic effect, such as p. ex. Digitalis glycosides, or diuretics. In addition, combinations with substances that act as antibiotics and anti-ulcer agents are advantageous, for example with H2 antagonists (eg ranitidine, cimetidine, famotidine, etc.), especially in the case of their application for the treatment of gastro-intestinal diseases. - intestinal. For a form of oral application, the active compounds are mixed with suitable additive materials, such as vehicle materials, stabilizers or inert diluents, and are carried by the usual methods to the appropriate presentation forms, such as tablets, dragees, nestable capsules, and 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 such a context, the preparation can be carried out in the form of both dry and wet granules. Suitable vehicle materials or oily solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are p. ex. water, ethanol or sugar solutions or mixtures of these. Other assistive materials, 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 substances customary for this, such as solubilizers, emulsifiers or other auxiliary materials, are brought into the form of a solution, suspension or emulsion. The compounds of Formula I and their physiologically compatible salts can also be lyophilized and the lyophilized materials obtained can be used e.g. ex. for the production of preparations for injection or infusion. Suitable solvents are p. ex. water, a physiological solution of sodium chloride or alcohols, p. ex. ethanol, propanol, glycerol, and together with it also sugar solutions 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 Formula I or of their physiologically compatible salts within a pharmaceutically innocuous solvent, such as especially ethanol or water, or a mixture of such solvents. The formulation, if necessary, may also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. One such 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 to be administered, or of its physiologically compatible salts, depends on each individual case and has to be adapted, as is usual to obtain an optimum effect, to the particularities of each case. individual case. Thus, this naturally depends on the frequency of administration and the intensity of the effect as well as the duration of the effect of the compounds used in each case for therapy or prophylaxis, but also depends on the type and severity of the disease that it must be treated as well as the sex, age, weight and individual responsiveness of the human or animal to be treated, and whether the therapy has to be performed in an acute or prophylactic manner. Usually, the daily dose of a compound of Formula I, in the case of its administration to a patient with a weight of approximately 75 kg, is from 0.001 mg / kg of body weight to 100 mg / kg of body weight, preferably from 0.01 mg / kg of body weight up to 20 mg / kg of body weight. The dose can be administered in the form of a single dose or 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 center, parenteral administration by injection or infusion can also be advantageous., p. ex. for a permanent intravenous infusion.

Experimental part List of abbreviations DMF N, N-dimethylformamide AE Ethyl ester of acetic acid P. f. Melting point (Unless otherwise stated, the melting points of the raw products are stated without being purified, the melting points of the respective pure substances may be perfectly well set) TA Ambient temperature THF Tetrahydrofuran.

Example 1: 3, 3-Dimethyl-l- (N-methyl-N-methylsulfonyl) amino-indane a) A solution of 25.0 g (0.156 mol) of 3,3-dimethyl-indan-1-one (Chem. Ber, 64, 1931, 4993) in 700 ml of methanol was stirred at 60 ° C for 8 h with 120.2 g (1.56 mol) of ammonium acetate and 69.1 g (1.1 mol) of sodium cyanoborohydride. The reaction mixture was adjusted to pH < 2 with dilute hydrochloric acid and concentrated by rotary evaporation. The residue was taken up in dilute hydrochloric acid, extracted with EA and the aqueous phase then made alkaline with a potassium carbonate solution and extracted with EA. After drying the organic phase with magnesium sulfate and concentrating in vacuo, 10.3 g of l-amino-3,3-dimethyl-indane were obtained. b) 4.0 g (34.7 mmol) of methanesulfonic acid chloride were added dropwise while cooling by ice to a solution of 5.1 g (31.6 mmol) of l-amino-3, 3-dimethyl. Intan and 12.8 g (126.4 mmol) of triethylamine in 100 ml of THF. After 2 h at RT 100 ml of water were added, the reaction mixture was concentrated to approximately 50 ml, 100 ml of water was added and the deposited precipitate was filtered off with suction, subsequently washed with water and dried in vacuo. 6.7 g of 3,3-dimethyl-1-methylsulfonylane-indane, -p. F. 117 - 119 ° C. c) A solution of 1.0 g (4.2 mmol) of 3,3-dimethyl-l-methylsulfonylamino-indane in 16 ml of DMF was added dropwise to a suspension of 0.15 g (5.1 mmol) ) of 80 percent sodium hydride in 10 ml of DMF, and stirring was continued at RT for 1 h. Then 0.59 g (4.2 mmol) of iodomethane was added and stirring was continued for 3 h at RT. After 3 ml of water had been added, the reaction mixture was completely concentrated in vacuo, the residue was taken up in EA and water and the organic phase was washed with dilute hydrochloric acid and with a saturated solution of sodium hydrogencarbonate. After drying over magnesium sulfate and concentrating, 0.5 g of 3,3-dimethyl-1- (N-methyl-N-methylsulfonyl) amino-indane; p. F. 71-73 ° C.

Example 2: 3, 3-Dimethyl-l- (N-ethylsulfonyl-N-methyl) amino-indane a) 4.44 g (34.7 mmol) of ethanesulfonic acid chloride were added dropwise while cooling by ice to a solution of 5.1 g (31.6 mmol) of l-amino-3, 3-dimethyl -inno (Example la) and 12.8 g (126 mmol) of triethylamine in 100 ml of THF After 2 h at RT the reaction mixture was concentrated in vacuo and the residue was taken up in water and EA. After drying the organic phase over magnesium sulfate and concentrating in vacuo, 6.4 g of 3,3-dimethyl-l-ethylsulfonylamino-indane were obtained. b) A solution of 1.0 g (4.2 mmol) of 3,3-dimethyl-l-ethylsulfonylamino-indane in 16 ml of DMF was added dropwise to a suspension of 0.15 g (5.1 mmol) ) of 80 percent sodium hydride in 10 ml of DMF and stirring was continued at RT for 1 h. After adding 0.59 g (4.2 mmol) of iodomethane, stirring was continued at RT for a further 3 h. Then 3 ml of water was added, the reaction mixture was completely concentrated by rotary evaporation and the residue was taken up in EA and water. The organic phase was washed with dilute hydrochloric acid and with a saturated solution of sodium hydrogencarbonate, dried with magnesium sulfate and concentrated in vacuo. 0.9 g of 3,3-dimethyl-1- (N-methyl-N-ethylsulfonyl) amino-indane was obtained in the form of an oil.

Example 3: 3, 3-Dimethyl-l- (N-hexyl-N-methylsulfonyl) amino-indane A solution of 1.0 g (4.2 mmol) of 3,3-dimethyl-1-methylsulfonylamino-indane (Example lb) 16 ml of DMF was added dropwise to a suspension of 0, 15 g (5.1 mmol) of 80 percent sodium hydride in 10 ml of DMF, and stirring was continued for 1 h at RT. 0.89 g (4.2 mmol) of 1-iodo-hexane was added and stirred for 3 h at RT. Then 3 ml of water was added, the reaction mixture was completely concentrated by rotary evaporation and the residue was taken up in EA and water. The organic phase was washed with dilute hydrochloric acid and saturated sodium hydrogencarbonate solution, dried with magnesium sulfate and concentrated by rotary evaporation. 1.1 g of 3,3-dimethyl-1- (N-hexyl-N-methylsulfonyl) amino-indane was obtained in the form of an oil. 1 H-NMR (200 MHz, CDC1. D [ppm] = 0.9 (t, 3H), 1.2 (s, 3H), 1.45 (s, 3H), 1.1-1.7 (m , 8H), 1.85 (dd, 1H), 2.25 (dd, 1H), 2.8-3.1 (m, 2H), 3.0 (s, 3H), 5.5 (t, 1H), 7.1-7.3 (m, 4H).

Example 4: 3, 3-Dimethyl-l- (N-ethylsulfonyl-N-hexyl) amino-indane A solution of 1.0 g (4.0 mmol) of 3,3-dimethyl-l-ethylsulfonylamino-indane (Example 2a) in 16 ml of DMF was added dropwise to a suspension of 0.15 g (5%). 1 mmol) of 80 percent sodium hydride in 10 ml of DMF and stirring was continued at RT for 1 h. 0.89 g (4.2 mmol) of 1-iodo-hexane was added and stirred for 3 h at RT. Then 3 ml of water was added, the reaction mixture was completely concentrated by rotary evaporation and the residue was taken up in EA and water. The organic phase was washed with dilute hydrochloric acid and with a saturated solution of sodium hydrogencarbonate, dried with magnesium sulfate and concentrated by rotary evaporation. 1.1 g of 3,3-dimethyl-1- (N-ethylsulfonyl-N-hexyl) amino-indane was obtained as an oil.

Example 5: N-Butyl-N- (1, l-dioxo-2,3-dihydro-lH-benzo [b] thiophen-3-yl) -methanesulfonamide a) 9.0 g (54 mmol) of benzothiophene-1,1-dioxide and 7.9 g (108 mmol) of n-butylamine were suspended in 130 ml of ethanol and heated for 3 h at the reflux temperature. The reaction mixture was concentrated in vacuo and 14.5 g of butyl- (1, l-dioxo-2,3-dihydro-lH-benzo [b] thiophen-3-yl) -amine was obtained as an oil. b) 6.63 g (57 mmol) of methanesulfonic acid chloride were added dropwise to a solution of 11.7 g (41 mmol) of butyl- (1, 1-dioxo-2,3-dihydroxy) benzo [b] thiophen-3-yl) -amine and 15.5 g (153 mmol) of triethylamine in 120 ml of THF and the reaction mixture was stirred at RT overnight. The THF was widely separated by distillation, the residue was diluted with 250 ml of water and the deposited precipitate was filtered off with suction. After drying under vacuum, 13.8 g of N-butyl-N- (1, l-dioxo-2,3-dihydro-lH-benzo [b] iofen-3-yl) methanesulfonamide were obtained; p. F. 171 - 173 ° C.

Example 6: N-Butyl-N- (6-nitro-l, l-dioxo-2,3-dihydro-lH-benzo [b] thiophen-3-yl) -me-anosulfonamide 0.5 g (1.6 mmol) of N-butyl-N- (1, l-dioxo-2,3-dihydro-lH-benzo [b] thiophen-3-yl) -methanesulfonamide (Example 5) were dissolved at -10 ° C in 5 ml of concentrated sulfuric acid and then mixed with 0.15 g (1.8 mmol) of sodium nitrate and stirred for 20 h at RT. The reaction mixture was poured into 50 ml of ice-water, stirring was continued for 30 min, filtered with suction, washed with water neutral and dried in vacuo. 0.5 g of N-butyl-N- (6-nitro-1, 1-dioxo-2,3-dihydro-1H-benzo [b] thiophen-3-yl) -methanesulfonamide; p. F. 52-55 ° C.

Example 7: 5-Fluoro-l- (N-methyl-N-methylsulfonyl) amino-indane a) 4.5 g (30 mmol) of 5-fluoro-1-indanone were heated at 80 ° C for 6 h in 20 ml of pyridine and 20 ml of ethanol with 2.3 g (33 mmol) of hydroxylamine hydrochloride. After the solvent had been distilled off, the residue was mixed with water and the deposited precipitate was filtered off with suction and dried in vacuo. 4.8 g of 5-fluoro-1-indanone oxime were obtained; p. F. 150 - 155 ° C. b) 1.6 g of 5-fluoro-1-indanone-oxime were hydrogenated at normal pressure and TA in 30 ml of methanol with Raney nickel as catalyst. After the catalyst was separated by filtration and the solvent was removed, the product was isolated as a hydrochloride by precipitation with ethereal hydrochloric acid. 0.6 g of 5-fluoro-l-indanylamine hydrochloride were obtained; p-. F. 245 - 247 ° C. c) 0.6 g of 5-fluoro-1-indanylamine hydrochloride was reacted analogously to Example 2a to form 0.6 g of 5-fluoro-1-ethylsulfonylamino-indane. d) 0.42 g of 5-fluoro-1- (N-methyl-N-methylsulfonyl) amino-indane were obtained from 0.6 g of 5-fluoro-1-ethylsulfonylamino-indane, analogously to Example 2b. in the form of an oil.

Example 8: R (+) -1- (N-Ethylsulfonyl-N-methyl) amino-indane a) From 3 g of R (-) - 1-amino-indane, 4.8 g of R (+) - 1-ethyl-sulfonylamino-indane were obtained analogously to Example 2b; p. F. 66 - 71 ° C, rotary power + 27.9 °. b) From 1.12 g of R (+) - 1-ethylsulphonylamino-indane, 0.87 g of R (+) - 1- (N-ethylsulphonyl-N-methyl) were obtained analogously to Example 2b. ) amino-indane in the form of an oil; rotary power + 15.9 °.

Example 9: S (-) -1- (N-Ethylsulfonyl-N-methyl) amino-indane a) From 5 g of S (+) - 1-amino-indane, 5.1 g of S (-) - 1-ethylsulphonylamino-indane, - p. were obtained analogously to Example 2b. F. 64 - 68 ° C, rotary power -29.5 °. b) From 1.12 g of S (-) -1-ethylsulphonylamino-indane, analogously to Example 2b, 0.89 g of S (+) - l- (N-ethylsulfonyl-N-methyl) amino were obtained - Indane in the form of an oil, - rotating power + 15,9 °.

Example 10: 3, 3-Dimethyl-6-nitro-l- (N-methyl-N-methylsulfonyl) -amino-indane a) By reduction of 3, 3-dimethyl-6-nitro-indan-1-one (Org. Prep.Procedure Int.10; 1978; 123) with sodium cyanoborohydride in the presence of ammonium acetate analogously to Example obtained l-amino-3, 3-dimethyl-6-nitro-indane. b) From 1.5 g of l-amino-3, 3-dimethyl-6-nitro-indane, 1.5 g of 3,3-dimethyl were obtained by reaction with methanesulfonic acid chloride, analogously to Example lb. -6-nitro-1-methylsulfonylamino-indane; p. F. 145 - 147 ° C. c) A solution of 0.15 g (0.5 mmol) of 3,3-dimethyl-6-nitro-1-methylsulfonylamino-indane, 0.12 g (0.5 mmol) of tert-butylimino-tris (dimethylamino) ) -phosphorane (phosphazene base) and 0.08 g (0.55 mmol) of iodomethane in 4 ml of DMF was stirred at RT overnight. After the solvent had been removed by distillation, the residue was taken up in EA and washed twice with water. After drying over magnesium sulfate and concentrate, 0.15 g of 3,3-dimethyl-6-nitro-l- (N-methyl-N-methylsulfonyl) amino-indane; p. F. 180 - 182 ° C.

Example 11: 3, 3-Dimethyl-6-nitro-l- (N-butyl-N-methylsulfonyl) -amino-indane The compound was obtained by alkylation of 3,3-dimethyl-6-nitro-1-methylsulfonylamino-indane with 1-iodo-butane analogously to Example 10c. P. f. 110 - 112 ° C.

Example 12: 3, 3-Dimethyl-6-nitro-l- [N- (4-pyridylmethyl) -N-methylsulfonyl] amino-indane The compound was obtained by alkylation of 3, 3-dimethyl-6-nitro-l-methylsulfonylamino-indane with 4-pyridylmethyl chloride hydrochloride analogously to Example 10c, however the double molar amount of the phosphazene base was employed.

Example 13: 6-Butoxy-3, 3-dimethyl-l- (N-methyl-N-methylsulfonyl) -amino-indane a) To a solution of 5.5 g (0.19 mol) of 80% sodium hydride in 250 ml of DMF was added dropwise under nitrogen a solution of 28.5 g (0.16 mol) of 6-hydroxy-3, 3-dimethyl-indan-1-one (J. Org. Chem. 19; 1954; 305) in 200 ml of DMF. After 1 h at RT, 30.4 g (0.17 mol) of 1-iodobutane was added and stirred for 2 h at RT. After the solvent had been distilled off in vacuo, the residue was taken up in EA and water and the organic phase was washed consecutively with dilute hydrochloric acid and dilute sodium hydroxide solution. 31.6 g of 6-butoxy-3, 3-dimethyl-indan-1-one were obtained. b) A solution of 1.0 g (4.3 mmol) of 6-butoxy-3, 3-dimethyl-indan-1-one, 1.9 g (30 mmol) of sodium cyanobotohydride and 3.3 g ( 43 mmol) of ammonium acetate in 30 ml of methanol was heated at 60 ° C for 5 h. After adding some water, the methanol was removed in vacuo and the residue was mixed with EA and hydrochloric acid. The aqueous acid phase was separated, made alkaline with sodium hydroxide solution and extracted with EA. 0.4 g of l-amino-6-butoxy-3, 3-dimethyl-indane were obtained. c) From 2.0 g of l-amino-6-butoxy-3, 3-dimethyl-indane, 2.1 g of 6-butoxy-3, 3-dimethyl-l- were obtained analogously to Example lb. Methylsulfonylamino-indane. d) By alkylation of 0.5 g of 6-butoxy-3, 3-dimethyl-l-methyl-sulfonylamino-indane with iodomethane, analogously to Example lc, 0.5 g of 6-butoxy-3, 3- were obtained dimethyl-1- (N-methyl-N-methylsulfonyl) amino-indane in the form of an oil.

Example 14: 6-Butoxy-3, 3-dimethyl-1- (N-ethyl-N-methylsulfonyl) -amino-indane The compound was obtained in the form of an oil by alkylation of 6-butoxy-3, 3-dimethyl-1-methylsulfonylamino-indane (Example 13c) with iodoethane, analogously to Example 1c.

^ -NMR (CDCI3): d [ppm] = 1.0 (t, 3H), 1.2 (s, 3H), 1.2 (t, 3H), 1.4 (s, 3H), 1.3-1.8 (m, 4H), 1.9 (dd, 1H), 2.25 (dd, 1H), 3.0 (s, 3H), 3.1 (m, 2H), 3.95 (t, 2H), 5.45 (dd, 1H), 6.9 (m, 2H), 7.05 (d, 1H).

Pharmacological research < IsK channels from human beings, rats or guinea pigs were expressed in Xenopus oocytes. For this, Xenopus Laevis oocytes were isolated and defoliated first. Next, RNA encoding IsK synthesized in vi tro was injected into these oocytes. After expression of IsK proteins for 2-8 days, the current intensities of IsK were measured in the oocytes with the volta e-Clamp technique of two microelectrodes. IsK channels were activated in this case as a rule with power surges at -10 mV that lasted 15 s. The bath was swept therethrough with a solution having the following composition: 96 mM NaCl, 2 mM KCl, 1.8 mM CaCl 2, 1 mM MgCl 2, 5 mM HEPES (titrated with NaOH at pH 7.5). These experiments were carried out at room temperature. For the collection of the data and the analysis were used: Amplifiers Geneclamp (Axon Instruments, Foster City, USA) and alternating current DC converters and MacLab Software (ADInstruments, Castle Hill, Australia). The substances according to the invention were tested by adding them in different concentrations to the bath solution. The effects of the substances were calculated as a percentage inhibition of the IsK control current, which was obtained when no substance was added to the solution. The data were then extrapolated with the Hill equation, in order to determine the IC50 inhibitory concentrations for the respective substances.

Bibliography; A.E. Busch, H.-G. Kopp, S. Waldegger, I. Samarzija, H. Sußbrich, G. Raber, K. Kuneelmann, J.P. Ruppersberg and F. Lang; "Inhibition of both exogenously expressed IsK and endogenous K + channels in Xenopus oocytes by isosorbiddini-try"; J. Physiol. 491 (1995), 735-741; T. Takumi, H. Ohkubo and S. Nakanishi; "Cloning of a membrane protein that induces a 'slow voltage-gated potassium current"; Science 242 (1989), 1042-1.045; M.D. Varnum, A.E. Busch, C.T. Bond, J. Maylie and J.P. Adelman; "The minK channel underlies the cardiac potassium current and mediates species-specific responses to protein kinase"; C. Proc. Nati Acad. Sci. USA 90 (1993), 11,528-11,532.

In the manner described, using the human IsK protein, the following IC50 values were determined for the compounds according to the invention:

Claims (21)

1. CLAIMS 1. - Compounds of Formula I, where they mean: R (l) and R (2) independently of one another, hydrogen, CF3, alkyl j with 1, 2, 3, 4, 5 or 6 C atoms: R (2) and R (9) in common a bond, - or R (2) -OR (10a), when X means -CR (22) R (23) -; R (l a) hydrogen, acetyl or alkyl having 1, 2 or 3 C atoms; R (3) R (10b) -CnH2n-NR (ll) - or R (10b) -CnH2n-, a CH2 group in the CnH2n groups being able to be replaced by -O-, -CO-, -S-, -SO -, -S02- or -NR (12a) -; R (12a) hydrogen, methyl or ethyl, - R (10b) methyl, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (ll) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (10b) and R (ll) in common, a link, as long as n is greater than 2; or R (3) in common with R (4) 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 -0-, -CO -, -S-, -SO-, -S02- or -NR (12a) -; R (12a) hydrogen, methyl or ethyl; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being replaced by -0-, -CH = CH-, -C = -C-, -CO-, -C0-0-, -O -CO-, -S-, -SO-, -S02-, -NR (14) - or -C0NR (14) -, - R (14) hydrogen, alkyl with 1, 2 or 3 C atoms, -CyH2y -OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl; and 2 or 3; R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -NR (15) R (16), -CONR (15) R (16), - OR (17), -COOR (17), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms; wherein the phenyl and the heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -O-, -S-, -NH-, -N (CH, ) - or -N (benzyl)) -, - R (17) hydrogen, alkyl having 1, 2 or 3 carbon atoms; -CzH2zOR (12c); R (12c) hydrogen, methyl or ethyl, -z 2 or 3; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R (5), R (6), R (7) and R (8), independently of each other, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -CN, -CF3, -C, F5, -C3F7, -N3, -N02, -Y-C3H2s-R (18), phenyl, thienyl , furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl, thienyl, furyl and the heterocycle containing N being unsubstituted or substituted or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfoylninylamino; Y -0-, -CO-, -C0-0-, -0-CO-, -S-, -SO-, -so2-, -0-S02-, -SO2NR (10c) - or -CONR (lOc) ) -, the connection being made with the fundamental framework in each case through the atom on the left, - (R (10c) hydrogen or alkyl with 1, 2 or 3 C atoms, zero, 1, 2, 3, 4, 5 or 6, - R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -OR (21), -C00R (21), -NR (15a) R (16a), -CONR (15a) R (16a), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, being able to the phenyl and the heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, -R (15a) and R (16a) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; or R (15a) and R (16a) in common , a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3) - or -N (benzyl) -; R (21) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, -X-CR (22) R (23) -, -0-, -NR (24) -, -S-, -SO-, -S02 -; R (22) and R (23) independently of one another, hydrogen, CF 3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms; R (24) hydrogen, alkyl having 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, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as its physiologically compatible salts.
2. 2. Compounds of Formula I according to claim 1, in which they mean: R (l) hydrogen; R (2) hydrogen or -OR (10a); R (10a) hydrogen, acetyl or alkyl having 1, 2 or 3 carbon atoms; or R (2) and R (9) in common, a link; R (3) R (10b) -CnH2n-NR (ll) - or R (10b) -CnH2n-, with a CH2 group in the CnH groups, n being replaced by -0-, -CO-, -S-, -SO-, -S02- or -NR (12a) -; R (12a) hydrogen, methyl or ethyl; R (10b) methyl, cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (ll) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 C atoms; or R (10b) and R (ll) in common, a link, as long as n is greater than 2; or R (3) in common with R (4) 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 -0-, -CO -, -S-, -SO-, -S02- or -NR (12a) -; R (12a) hydrogen, methyl or ethyl, - R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -0-, -CH = CH-, -C = C-, -CO -, -C0-0-, -O-CO-, -S-, -SO-, -S02-, -NR (14) - or -CONR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 C atoms; -CyH2y-OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl; and 2 or 3, - R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or a heterocyclic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl being and the heterocycle containing N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -O-, -S-, -NH-, -N (CH3) - or -N (benzyl) -; R (17) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CzH220R (12c); "R (12c) hydrogen, methyl or ethyl; z 2 or 3; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19 or 20, R (, 5), R (6), R (7) and R (8) independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -CN, -CF3, -C2F5, -C3F7, -N3, -N02, -Y-C3H2s-R (18), phenyl, thienyl, furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, with phenyl, thienyl, furyl and the heterocycle containing N be unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulphamoyl, methylsulfonyl and methylsulfonylamino; Y -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -so2-, -0-S02-, -SO2NR (10c) - or -CONR (lOc) ) -, making the connection with the fundamental framework in each case through the atom on the left, - R (10c) hydrogen or alkyl with 1, 2 or 3 C atoms; ? zero, 1, 2, 3, 4, 5 or 6; R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5, 6, 7 or 8 C atoms, -0R (21), -C0OR (21), -NR (15a) R ( 16a), -CONR (15a) R (16a), phenyl, or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle being contains N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15a) and R (16a) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15a) and R (16a) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3) - or - (benzyl) -; R (21) hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond; X-CR (22) R (23) -; R (22) and R (23) independently of one another, hydrogen, CF 3, alkyl with 1, 2, 3, 4, 5 or 6 C atoms; as well as its physiologically compatible salts.
3. 3. Compounds of Formula I according to claims 1 or 2, in which they mean: R (l) hydrogen, -R (2) hydrogen or -OR (lOa); R (10a) hydrogen, acetyl or alkyl having 1, 2 or 3 carbon atoms, - or R (2) and R (9) in common, a bond; R (3) R (10b) -CnH2n-, R (10b) methyl, cycloalkyl with 3, 4, 5 or 6 C atoms, CF3, C2F5 or C3F7; n zero, 1, 2, 3, 4 or 5; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being replaced by -O-, -CO-, -CO-0-, -O-CO-, -NR (14) - or -C0NR (14) -, - R (14) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CyH2y-OR (12b), -CyH2y-NR (12b) 2; R (12b) hydrogen, methyl or ethyl, -, and 2 or 3; R (13) CH3, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5 or 6 C atoms, -NR (15) R (16), -CONR (15) R (16), -0R (17) , -C00R (17), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8, 6, 9 C atoms, the phenyl being and the heterocycle containing N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, NI-2 'OH, methyl, ethyl, methoxy, dimethylamino, sulphamoyl, methylsulfonyl and ethylsulfonylamino; R (15) and R (16) independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C atoms; or R (15) and R (16) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -0-, -S-, -NH-, -N (CH3) - or -N (benzyl) -; R (17) hydrogen or alkyl having 1, 2 or 3 C atoms; r zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R (5), R (6), R (7) and R (8) independently of one another, hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3 , 4, 5 or 6 C atoms, -CN, -CF3. -C2F5, -C3F7, -N02, -Y-C3H2s-R (18), phenyl, thienyl, furyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms C, the phenyl, thienyl, furyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, H2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -so2-, s zero, 1, 2, 3, 4, 5 or 6; R (18) hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl with 3, 4, 5 or 6 C atoms; -OR (21), -COOR (21), -NR (15a) R (16a), -CONR (15a) R (16a), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, NH2, OH , methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, -R (15a) and R (16a) independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or R (15a) and R (16a) in common, a chain of 4 or 5 methylene groups, of which a CH2 group can be replaced by -O-, -S-, -NH-, -N (CH3) - or -N (benzyl) -; R (21) alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, -X-CR (22) R (23) -; R (22) and R (23) independently of one another, hydrogen, CF 3, alkyl with 1, 2 or 3 C atoms; as well as its physiologically compatible salts.
4. 4. Compounds of Formula I according to one or more of claims 1 to 3, in which they mean: R (l) hydrogen; R (2) hydrogen or -OR (10a), -R (10a) hydrogen or methyl; or R (2) and R (9) in common, a link; R (3) R (10b) -CnH2n-, R (10b) methyl; n zero, 1 or 2; R (4) R (13) -CrH2r, with a CH2 group of the CrH2r group being replaced by -0-, -CO-, -C0-0- or -C0NR (14) -; R (14) hydrogen, alkyl having 1, 2 or 3 carbon atoms, -CyH2y-OR (12b); - R (12b) hydrogen, methyl or ethyl; and 2 or 3; R (13) CH3, CF3 or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, "~ the heterocycle containing N being unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; r zero, 1, 2, 3, 4, 5, 6, 7 or 8; R (5), R (7) and R (8) hydrogen, R (6) hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, cycloalkyl with 3, 4, 5 or 6 C atoms , -CN ', -CF ,, -C2Ff), -C3F7, -NO ,, -YC..Hi (.- R (18), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5 , 6, 7, 8 or 9 C atoms, the phenyl being and the heterocycle containing N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy: Y -0-; s 1, 2, 3, 4, 5 or 6; R (18) hydrogen, CF3, -OR (21), phenyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, the phenyl and the heterocycle being contains N unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF,, N02, CN, methyl and methoxy; R (21) alkyl having 1, 2 or 3 carbon atoms; R (9) hydrogen or in common with R (2) a bond, -X-CR (22) R (23) -; R (22) and R (23) independently of one another, CF3 or methyl; as well as its physiologically compatible salts.
5. 5. Compounds of Formula I according to one or more of claims 1 to 4, in which they mean: R (l) hydrogen; R (2) hydrogen; R (3) methyl or ethyl; R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-; R (13) CH 3 or CF 3; r zero, 1, 2, 3, 4, 5 or 6, -R (5), R (7) and R (8) hydrogen; R (6) F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, -CN, -CF3, -N02, -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; And -0-; S 1, 2, 3, 4, 5 0 6; R (18) hydrogen, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; R (9) hydrogen; X-CR (22) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts.
6. 6. Compounds of Formula I according to one or more of claims 1 to 4, in which they mean: R (l) hydrogen; R (2) OH; R (3) methyl or ethyl, -R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -O-, - R (13) CH3 or CF3; r zero, 1, 2, 3, 4, 5 or 6, -R (5), R (7) and R (8) hydrogen; R (6) F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C atoms, -CN, -CF3, -N02, -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; Y -0-, - S 1, 2, 3, 4, 5 0 6; R (18) hydrogen, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; R (9) hydrogen; X-CR (22) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts.
7. 7. Compounds of Formula I according to one or more of claims 1 to 4, in which they mean: R (l) hydrogen; R (2) in common with R (9), a bond; R (3) methyl or ethyl, -R (4) R (13) -CrH2r, a CH2 group of the CrH2r group being able to be replaced by -0-; R (13) CH3 or CF3; r zero, 1, 2, 3, 4, 5 or 6; R (5), R (7) and R (8) hydrogen; R (6) F, Cl, Br, alkenyl having 1, 2, 3, 4 or 5 carbon atoms, -CN, -CF3 or -N02, -Y-C3H2s-R (18) or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy; I-; S 1, 2, 3, 4, 5 0 6; R (18) hydrogen, CF3 or phenyl which is unsubstituted or substituted with 1 or 2 substituents, selected from the group consisting of F, Cl, Br, CF3, N02, CN, methyl and methoxy, -X-CR (22 ) R (23) -; R (22) and R (23) methyl; as well as its physiologically compatible salts.
8. 8. Compounds of Formula I according to one or more of claims 1 to 7 and their physiologically compatible salts for their application as medicaments.
9. 9. Pharmaceutical preparation, which contains an effective amount of at least one compound of Formula I according to one or more of claims 1 to 7 and / or a physiologically compatible salt thereof as active substance, together with carrier materials and pharmaceutically acceptable additives and optionally also one or more other pharmacologically active substances.
10. 10. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament with a K + channel blocking effect intended for therapy and the prophylaxis of diseases mediated by K + channels.
11. 11. Use of a compound of Formula I according to one of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament for the inhibition of gastric acid secretion.
12. 12. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament intended for the therapy or prophylaxis of stomach ulcers or of the intestinal region.
13. 13. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament intended for the therapy or prophylaxis of esophagitis of Reflux.
14. 14. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament intended for the therapy or prophylaxis of diseases of diarrhea.
15. 15. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medication for the therapy or prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias.
16. 16. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament for the therapy or prophylaxis of disorders of the heart rhythm, which can be suppressed by prolonging the action potential.
17. 17. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter. .
18. 18. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament for the therapy or prophylaxis of reentry arrhythmias or for the inhibition of sudden cardiac death as a consequence of ventricular fibrillation.
19. 19. Use of a compound of Formula I according to one or more of claims 1 to 7 and / or of a physiologically compatible salt thereof, for the preparation of a medicament for the therapy of heart failure.
20. 20. Use of a compound of Formula I according to one or more of claims 1 to 2 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, of reflux esophagitis, of diseases of diarrhea, for therapy or prophylaxis of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial flutter and reentry arrhythmias, or for the inhibition of sudden cardiac death as a consequence of ventricular fibrillation.
21. 21. - Pharmaceutical preparation, which contains an effective amount of at least one compound of Formula I according to one or more of claims 1 to 6, and / or of a physiologically compatible salt thereof and of a beta-blocker as active substances , together with pharmaceutically acceptable vehicle and additive substances.