HRP980098A2 - Sulfonamido substituted condensed, seven-membered ring compounds, their use as medicines and pharmaceutical preparations containing them - Google Patents

Description

The invention relates to compounds of formula I

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in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the following meanings, on their production and their use, especially as drugs. These compounds affect potassium or Ix channels that open with cyclic adenosine monophosphate (cAMP) and are extremely suitable as active substances of drugs, for example for the prophylaxis and therapy of diseases of the cardiac circulation, especially arrhythmias, for the treatment of ulcers in the stomach and intestines or for treatment of diseases with diarrhea.

In recent years, in the chemistry of medicines, there has been intensive work on the class of 4-acylaminochroman derivatives, i.e. their homologues and analogues. A prominent representative of this class is cromakalim of formula A, and an example of a homolog is compound of formula B (J. Chem. Soc., Perkin Trans. 1, 1991, 2763).

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In the case of chromakali and other related derivatives of 4-acylamino-chromane, it is made with compounds with a relaxing effect on smooth muscle organs, so they are used to reduce elevated blood pressure due to relaxation of the muscles of blood vessels and treat asthma due to relaxation of the smooth muscles of the respiratory tract. All these preparations have in common that they act at the cellular level, for example at the level of smooth muscle cells, where they lead to the opening of certain ATP-sensitive K+ channels. The increase in the negative charge in the cell ("hyperpolarization"), induced by the release of K+ ions, acts through the secondary mechanism of increasing the concentration of intracellular Ca2+ and thus works against the activation of the cell, which for example leads to muscle contraction.

From these acetylamino derivatives, the compounds of formula I according to the invention differ structurally, especially by replacing the acylamino group with a sulfonylamino functional group. While cromopotassium (formula A) as well as the homologue of formula B and analogous acylamino compounds act as openers of ATP-sensitive K+ channels, the compounds according to the invention of formula I with the sulfonamide structure do not show any activity in terms of opening these K+(ATP)-channels, but surprisingly strongly and specifically block (close) K+-channels, which open with cyclic adenosine aminophosphate (cAMP) and fundamentally differ from the aforementioned K+(ATP)-channels. Recent research shows that this K+(cAMP)-channel, identified on the colon tissue, is very similar, perhaps even identical, to the Iks-channel identified on the heart muscle. Indeed, the compounds according to the invention of formula I can be shown to have a strong blocking effect on the IKs-channel in guinea pig cardiomyocytes, as well as on the IsK-channels expressed in xenopus oocytes. Because of this blocking of K+(cAMP)-channels, i.e. IKs-channels, the compounds according to the invention develop a pharmacological action of high therapeutic value in the living organism.

In addition to the above-mentioned chromalim derivatives, i.e. acyl-aminochroman, compounds with a 4-sulfonylaminochroman structure are also described in the literature, which, however, clearly differ from the compounds according to the invention of formula I in terms of structure or biological activity. Thus, EP-A-315 009 describes chroman derivatives with a 4-phenylsulfonylamine structure, which are characterized by antithrombotic and antiallergic properties. EP-A-389 861 and EP-A-370 901 describe derivatives of 3-hydroxychroman with one sulfonylamino group, which are described as K+(ATP)-channel activators, i.e. they act on the central nervous system. Further derivatives of 4-sulfonylamino-chroman are described in Bioorg. Honey. Chem. Lett. 4 (1994), 769-773: "N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburide insensitive smooth muscle relaxants to potent smooth muscle contractors".

The proposed invention relates to compounds of formula I,

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where

X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)-, -NR(6)-, -CO- or -CR(1)R(7);

R(1) and R(2) independently of each other represent hydrogen, CF3, C2F5, C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 a substituent selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; or

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

R(6) is hydrogen or -CnH2n-R(8), whereby one CH2-group in the CnH2n group can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO -O-, -O-CO-, -S-, -SO-, -SO2-, -NR(9)- or -CONR(9)-;

R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R(8) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazine -1-yl, pyridyl, thienyl, imidazolyl or phenyl,

whereby pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

X2 represents -CR(1)R(2)- or -CR(2)R(10)-; or

X2 if X3 and X1 represent -CR(1)R(2)-, also represents -O-, -S-, -SO-, -SO2- or -NR(6)-,

wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1;

R(10) together with R(7) forms one bond;

X 3 is -CR(1)R(2)-; or

X3 if X2 and X4 represent -CR(1)R(2)-, also represents -O-, -S-, -SO-, -SO2- or -NR(6)-,

wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)-, -CH(OR(30))- or -CR(2)R(11)-,

wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1;

R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms;

R(11) together with R(5) forms one bond;

Y1, Y2, Y3 and Y4 independently represent -CR(12)- or N,

whereby at most 2 of the groups Y1, Y2, Y3 and Y4 can simultaneously be N;

residues R(12) are independently hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4, or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms -atom, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, J , CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-;

R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

m is zero, 1, 2, 3, 4, 5 or 6;

R(13) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, -NR(15)R(16)-, -CONR(15)R(16 )-, -OR(30a), phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms,

wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-;

R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or

Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-;

residues R(12) are defined independently of each other as Y1, Y2, Y3 and Y4;

R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-,

whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-;

R(19) is hydrogen, methyl or ethyl;

R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, CF3, C2F5 or C3F7;

x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or

R(18) and R(17) together form one bond, if x is not less than 3; or

R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or

R(3) together with R(4) represents an alkylene chain having 3, 4, 5, 6, 7 or 8 carbon atoms;

wherein one CH2-group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO- or -SO2-;

R(4) represents -CrH2r-R(20),

whereby one CH2-group in the group CrH2r can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(21)- or -CONR(21)-;

R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

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

R(20) represents hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with -N(benzyl)-;

R(5) represents hydrogen or together with R(11) forms one bond;

in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

Preferred compounds of formula I are those in which X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , R(3), R(4) and R(5) have the meanings given above, wherein, however, one of residues R(3) and R(4), especially the residue R(5) has a meaning other than hydrogen, and further compounds of formula I in which both residues R(3) and R(4) have a meaning other than hydrogen, in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

Compounds of formula I in which

X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)- or -NR(6)-;

R(1) and R(2) independently of each other represent hydrogen, CF3, C2F5, C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 a substituent selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; or

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

R(6) is hydrogen or -CnH2n-R(8),

whereby one CH2-group in the group CnH2n can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(9)- or -CONR(9)-;

R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

n is zero, 1, 2, 3, 4, 5, 6, 7 or 8;

R(8) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl , pyridyl, thienyl, imidazolyl or phenyl,

wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

X 2 represents -CR(1)R(2)-;

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X3 is -CR(1)R(2)-,

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)- or -CH(OR(30))-;

wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1;

R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms;

R(11) together with R(5) forms one bond;

Y1, Y2, Y3 and Y4 independently represent -CR(12)- or N,

whereby at most 2 of the groups Y1, Y2, Y3 and Y4 can simultaneously be N;

the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, cycloalkyl having 3, 4, 5 or 6 C-atoms, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-;

R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

m is zero, 1, 2, 3, 4, 5 or 6;

R(13) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(15)R(16)-, -CONR(15)R(16)-, -OR(30a) , phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-;

R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or

Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-;

residues R(12) are defined independently of each other as indicated by Y1, Y2, Y3 and Y4;

R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-,

whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-;

R(19) is hydrogen, methyl or ethyl;

R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, CF3, C2F5 or C3F7;

x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or

R(18) and R(17) together form one bond, if x is not less than 3; or

R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or

R(3) together with R(4) represents an alkylene chain having 3, 4, 5, 6, 7 or 8 carbon atoms;

wherein one CH2-group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO- or -SO2-;

R(4) represents -CrH2r-R(20)-,

whereby one CH2-group in the group CrH2r can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(21)- or -CONR(21)-;

R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

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

R(20) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms,

wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with -N(benzyl)-;

R(5) represents hydrogen or together with R(11) forms one bond;

in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

Particular preference is given to compounds of formula I in which

X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)- or -NR(6)-;

R(1) and R(2) independently represent hydrogen, CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or

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

R(6) is hydrogen or -CnH2n-R(8),

whereby one CH2-group in the group CnH2n can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(9)- or -CONR(9)-;

R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

n is zero, 1, 2, 3, 4, 5, 6, 7 or 8;

R(8) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl , imidazolyl or phenyl,

wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

X 2 represents -CR(1)R(2)-;

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X3 is -CR(1)R(2)-,

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)- or -CH(OR(30))-;

wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1;

R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms;

R(11) together with R(5) forms one bond;

Y1, Y2, Y3 and Y4 independently represent -CR(12)-;

the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, cycloalkyl having 3, 4, 5 or 6 C-atoms, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-;

R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

m is zero, 1, 2, 3, 4, 5 or 6;

R(13) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(15)R(16)-, -CONR(15)R(16)-, -OR(30a) , phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-;

R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or

Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-;

residues R(12) are defined independently of each other as indicated by Y1, Y2, Y3 and Y4;

R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-,

whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-;

R(19) is hydrogen, methyl or ethyl;

R(17) is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, C2F5 or C3F7;

x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or

R(18) and R(17) together form one bond, if x is not less than 3; or

R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or

R(4) represents -CrH2r-R(20)-,

whereby one CH2-group in the group CrH2r can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(21)- or -CONR(21)-;

R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R(20) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7 or 8, or 9 C-atoms,

wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or

R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-;

R(5) represents hydrogen or together with R(11) forms one bond;

in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

Particular preference is given to compounds of formula I in which

X1 represents -O- or -CR(1)R(2)-;

R(1) and R(2) independently represent hydrogen, CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

X 2 represents -CR(1)R(2)-;

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X3 is -CR(1)R(2)-,

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

X4 represents -CR(1)R(2)- or -CH(OR(30))-;

wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1;

R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms;

Y1, Y2, Y3 and Y4 independently represent -CR(12)-;

the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, CN, CF3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-;

R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

m is zero, 1, 2 or 3;

R(13) represents hydrogen, CF3, -NR(15)R(16)-, phenyl, piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl or imidazolyl;

R(3) represents R(17)-CxH2x-,

R(17) is methyl;

x is zero, 1, 2 or 3;

R(4) represents –CrH2r-R(20),

whereby one CH2 group in the CrH2r group can be replaced by -O-, -CO-, -CO-O-, -NR(21)- or -CONR(21)-;

R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r is zero, 1, 2, 3, 4, 5 or 6;

R(20) represents methyl, CF3 or pyridyl;

R(5) represents hydrogen;

in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

A very particular and special advantage is given to the compounds of formula I in which

X1 represents -O-;

X2 represents -CR(1)R(2)-,

R(1) and R(2) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms;

X 3 is -CH 2 - or -C(CH 3 ) 2 ;

X 4 is -CH 2 -;

Y1 is CH;

Y 2 is CH;

Y 4 is CH;

Y3 is -CR(12)-;

R(12) represents F, Cl, Br, alkyl having 1, 2 or 3 carbon atoms, CN, CF3, NO2, -Z-CmH2m-R(13);

Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)- or -CONR(14)-;

R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

m is 1, 2 or 3;

R(13) represents hydrogen, CF3, pyridyl or phenyl;

R(3) represents R(17)-CxH2x-,

R(17) is methyl;

x is 0, 1 or 2;

R(4) represents -CrH2r-R(20),

whereby one CH2-group in the group CrH2r can be replaced by -O-, -CO-O-, -O-CO- or -CONR(21)-;

R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

r is zero, 1, 2, 3, 4, 5 or 6;

R(20) represents methyl, CF3;

R(5) represents hydrogen;

in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts.

Alkyl residues and alkylene residues can have a straight or branched chain. This also applies to alkylene residues of the formulas CnH2n, CmH2m, CxH2x and CrH2r. Alkyl radicals and alkylene radicals can also have a straight or branched chain when they are substituted or contained in other radicals, for example in an alkoxy radical or in an alkylmercapto radical or in a fluorinated alkyl radical. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl. Divalent residues derived from these residues, e.g. 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 alkene residues. Examples of acyl residues are formyl, acetyl, propionyl, n-butyryl or isobutyryl.

The aromatic systems 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5- imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -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- or 5-yl, 1,3,4-oxadiazol-2-yl or 5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-iso-thiazolyl, 1 ,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-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-quinolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8 - phthalazinyl.

Particularly preferred nitrogen-containing heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Thienyl also stands for 2- as well as 3-thienyl.

Monosubstituted phenyl residues can be substituted in the 2-, 3- or 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position. The corresponding analogy in this sense also applies to heterocycles containing a nitrogen or a thiophene residue.

In the case of disubstituted residues, the substituents can be the same or different.

If the residues R(1) and R(2) together form an alkylene residue, then these residues together with the carbon atom carrying them form a ring, which has one carbon atom in common with the seven-membered ring in formula I, so it is therefore a spiro compound. If R(7) and R810) together form one bond, then there is a double bond between the groups X1 and X2. Correspondingly, if R(5) and R(11) together form a single bond, there is a double bond between the X4 group and the carbon atom carrying the residue R(3)-SO2-NR(4)-. If R(17) and R(18) together form one bond, then the group R(17)-CxH2x-NR(18)- represents primarily a nitrogen-containing heterocycle connected via a nitrogen atom. If R(17) and R(18) together form one bond, and the group R(17)-CxH2x-NR(18)- represents a nitrogen-containing heterocycle connected via a nitrogen atom, this nitrogen-containing heterocycle is preferably four-membered ring or a ring larger than a four-membered ring, eg a five-, six- or seven-membered ring. If Y1 and Y2 together represent a sulfur atom, then the structural unit -Y2=Y1- represents -S-, so in that case the seven-membered ring in formula I is annealed to the thiophene ring.

If the compounds of formula I contain one or more acidic or basic groups, i.e. one or more basic heterocycles, then also corresponding physiologically or toxicologically tolerable salts are the subject of the invention, especially pharmaceutically usable salts. Thus, the compounds of formula I, which carry acidic groups, e.g. one or more COOH groups, can be used, for example, as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts, e.g. calcium or magnesium salts, or as ammonium salts salts, eg as salts with ammonia or organic amines. Compounds of formula I, which carry one or more basic, i.e. groups that can be protonated, or if they contain one or more basic heterocyclic rings, they can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleinates, fumarates, malates, gluconates, etc. If the compounds of formula I contain molecules with both acidic and basic groups, then in addition to the mentioned salt forms, the invention also includes internal salts, so-called betaines. From the compounds of formula I, salts can be obtained by usual procedures, for example by cleaning with an acid or base in a solvent or in a dispersing agent or also by anion exchange from other salts.

With certain substitution, the compounds of formula I can exist in stereoisomeric forms. If the compounds of formula I contain one or more asymmetric centers, then they can independently have an S- or R-configuration. The invention includes all possible stereoisomers, eg enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, eg enantiomers and/or diastereomers in any proportions. The invention also includes enantiomers, for example in enantiomerically pure form, as well as left- and right-handed antipodes, also in the form of mixtures of both enantiomers in different proportions or in the form of racemates. In case of cis/trans-isomerism, the invention covers both the cis-form, as well as the trans-form and their mixtures. Individual stereoisomers can be optionally produced by separating the mixture by conventional methods or, for example, by stereoselective synthesis. If there are mobile hydrogen atoms, the proposed invention also includes all tautomeric forms of the compounds of formula I.

Compounds of formula I can be produced by various chemical processes. Thus, the compound of formula I can be obtained by:

a) compound of formula IIa or formula IIb

[image]

where X1, X2, X3, X4, Y1, Y2, Y3, Y4 and R(5) have the meanings given above, and L is a nucleophilic leaving group, especially some common nucleophilic leaving group such as F, Cl, Br, J, methanesulfonyloxy or p-toluenesulfonyloxy, chemically converted in the usual way with sulfonamide or its salt of formula III

[image]

in which R(3) and R(4) have the meanings given above, and M is hydrogen or preferably a metal atom, especially preferably lithium, sodium or potassium, and in the case of chemical conversion with the compound of formula IIb, it can also be a trialkylsilyl residue, e.g. a trimethylsilyl radical; or to

b) compound of formula IV

[image]

in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(4) and R(5) have the above meanings,

chemically converted with a sulfonic acid derivative of formula V

[image]

in which R(3) has the meaning stated above, and W is a nucleophilic leaving group, such as, for example, fluorine, bromine, 1-imidazolyl, and especially chlorine; or to

c) compound of formula VI

[image]

wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(5) and M have the above meanings,

chemically converted in a manner known per se by an alkylation reaction with an alkylating agent of formula VII

R(4)-L VII

wherein R(4) is as defined above, excluding hydrogen, and L is as defined above; or to

d) in the compound of formula I

[image]

in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the meanings given above, in at least one of the positions Y1 to Y4, if a CH-group is found in the positions, an electrophilic substitution reaction is carried out, or a chemical conversion, for example alkylation or acylation, is carried out in at least one of the positions X1 to X4.

Process a) corresponds to the nucleophilic substitution of the starting group in the reactive cycle of formula IIa or IIb by means of sulfonamide or one of its salts of formula III. Due to the high nucleophilicity and high reactivity of sulfonamide present in salt form, when using free sulfonamide (formula III, M = H), it is useful to first produce a sulfonamide salt (formula III, M = metal cation) from it by the action of a base. If the free sulfonamide (formula III, M = H) is used, then the deprotonation of the sulfonamide to the salt is performed in situ. Such bases are primarily used that do not alkylate themselves or are alkylated only very slightly, such as sodium carbonate, potassium carbonate, sterically strongly hindered amines, e.g. dicyclohexylamine, N,N-dicyclohexyl-ethylamine, or other strong nitrogen bases of insignificant nucleophilicity , for example DBU (diazabicycloundecane), N,N',N'”-triisopropylguanidine, etc. In any case, other common bases can also be used for the reaction, such as potassium tert.butylate, sodium methylate, alkaline hydrogen carbonate, alkaline hydroxide, as for example LiOH, NaOH or KOH, or alkaline earth hydroxides, such as Ca(OH)2. In the case of chemical conversion of epoxide of formula IIb with trialkyl- or trimethylsilylsulfonamide of formula III, it is useful to carry out the reaction in the presence of fluoride, eg tetrabutylammonium fluoride.

It is done primarily in a solvent, especially preferably in polar organic solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetramethylurea (TMU), hexamethylphosphoric acid triamide (HMPT), tetrahydrofuran (THF). , dimethoxyethane (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, etc. However, it can also be carried out in polar protic solvents, such as e.g. water, methanol, ethanol, isopropanol, ethylene glycol or their oligomers and their corresponding semi-ethers or also their ethers. The reaction can also be carried out completely without solvent. The reaction is preferably carried out in the temperature range from -10 to +-140ºC, especially preferably in the range from 20 to 100ºC. In the most favorable way, procedure a) is also carried out under catalytic phase transfer conditions.

Compounds of the formula IIa can be obtained by methods known from the literature, for example from the corresponding alcohols (formula IIa, L = OH, R(5) = H) by the action of hydrogen halides of the formula HL (L = Cl, Br, J) or by the action of an inorganic acid halide (e.g. POCl3, PCl3, PCl5, SOCl2, SOBr2), or, for example, by radical halogenation of the corresponding compounds of formula IIa with L = H and R(5) = H with elemental chlorine or bromine or with a halogenating agent that can be radically activated, such as e.g. with N-bromosuccinimide (MBS) or sulfuryl chloride (SO2Cl2). In the case of radical halogenation, it is generally carried out in the presence of a radical chain starter, such as light rich in energy in the visible or ultraviolet wavelength range, or under the conditions of a chemical radical starter such as azodiiso-butyronitrile.

Compounds of formula IIa, in which X4 stands for -NR(11)- and R(5) together with R(11) represents one bond, are obtained, for example, from the corresponding lactams (formula IIa, L and R(5) together represent a carbonyl atom oxygen, X4 is NH) by the action of an inorganic halide (eg POCl3, PCl3, PCl5. SOCl2, SOBr2).

Compounds of formula IIb are obtained by methods known from the literature from corresponding olefins of formula IIc,

[image]

in which X1, X2, X3, Y1, Y2, Y3 and Y4 have the above meanings, e.g. by the action of a suitable inorganic or organic peroxide, such as H2O2 or m-chloro-perbenzoic acid, or by base-catalyzed cyclization of the corresponding bromohydrin, which can obtained from IIc, for example, by conversion with N-bromosuccinimide and water.

Epoxides of formula IIb can be obtained from olefins of formula IIc also in optically pure form by oxidation in the presence of a chiral Jacobsen catalyst, as described for example in Tetrahedron Lett., 32, 1991, 5055.

Procedure b) corresponds to the known and often applied reaction of a reactive sulfonyl compound of formula V, especially a chlorosulfonyl compound (W = Cl), with an amino derivative of the general formula IV, which gives the corresponding sulfonamide derivative of the general formula I. The reaction can also be carried out without a solvent, however reactions of this type, however, are most often carried out with the use of solvents. The reaction is primarily carried out with the use of a polar solvent, especially preferably in the presence of a base, which itself can be usefully used as a solvent, for example with the use of triethylamine or especially pyridine or its homologues. Suitable solvents are, for example, water, aliphatic alcohols, e.g. methanol, ethanol, isopropanol, sec.butanol, ethylene glycol, monoalkyl- and dialkyl ethers of monomeric or oligomeric ethylene glycols, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA as well as TMU and HMPT . This is generally done at a temperature from 0 to 160ºC, preferably from 20 to 100ºC.

Amines of formula IV are obtained by a process known from the literature from the corresponding carbonyl compounds of formula VIII,

[image]

wherein X1, X2, X3, X4, Y1, Y2, Y3 and Y4 have the above meanings and A represents oxygen, with ammonia or an amine of formula IX

R(4)-NH2 IX

in which R(4) has the stated meaning, under reductive conditions or under reductive catalytic conditions, preferably at elevated temperature and in an autoclave. First, by the condensation reaction of the ketone of formula VIII (A = oxygen) and the amine of formula IX, the Schiff base of formula VIII is formed in situ, where A represents R(4)-N=, which can be directly, i.e. without prior isolation, reductively convert to the amine of formula IV. However, it is also possible, by methods known from the literature, to produce Schiff's bases, which are formed as intermediates in the condensation reaction from compounds of formula VIII and IX (formula VIII, A represents R(4)-N=) and first isolate them, then in a special stage of conversion to compounds of formula IV with a suitable reducing agent, such as NaBH4, LiAlH4, NaBH3CN or by catalytic hydrogenation in the presence of, for example, Raney nickel or a noble metal such as palladium.

Compounds of formula IV, in which R(4) represents hydrogen, can be obtained first of all in a manner known from the literature, by oxime or oxymeter reduction (formula VIII, A stands for =N-OR, R = H or alkyl) or hydrazone (formula VIII, A stands for =N-NR2, R is eg H or alkyl), eg using a complex metal hydride or catalytic hydrogenation. The necessary oximes and hydrazones are produced in a known manner from ketones of formula VIII (A = oxygen) with hydrazine or one of its derivatives or, for example, with hydroxylamine hydrochloride under the conditions of splitting off water.

Process c) represents a known alkylation reaction of sulfonamide, that is, some of its salts (formula VI) with an alkylating agent (formula VII). Corresponding analogies of the reactions apply to procedure c), which has already been described in detail under the reaction conditions for procedure a).

The preparation of sulfonamide derivatives of formula VI and their precursors is already described in procedure b). The preparation of compounds for the alkylation of compounds of formula VII is carried out analogously to the procedures described in the literature, that is, to the procedures described in procedure a), primarily from the corresponding hydroxy compounds (formula VII, L = hydroxy).

Process d) corresponds to the further chemical conversion of compounds of formula I according to the invention into other compounds of formula I, for example by electrophilic substitution reaction in one or more positions marked with Y1 to Y4, if they mean CH groups. Favorable substitution reactions are

1. aromatic nitration for the introduction of one or more nitro groups, which in the following reaction can be partially or completely reduced to amino groups. Amino groups can again be converted into other groups in the following reactions, for example by the Sandmeyer reaction, for example for the introduction of cyano groups;

2. aromatic halogenation, especially for the introduction of chlorine, bromine or iodine;

3. chlorosulfonation, for example by the action of chlorosulfonic acid, to introduce a chlorosulfonic group, which in the following reaction can be converted into another group, for example a sulfonamide group;

4. Friedel-Crafts acylation reaction for the introduction of an acyl residue or sulfonyl residue by the action of a suitable acid chloride in the presence of a Lewis acid as a Friedel-Crafts catalyst, preferably in the presence of anhydrous aluminum chloride.

As further chemical transformations of compounds according to the invention of formula I, reactions in positions X1 to X4 are possible, for example. Thus, for example, the compounds according to the invention of the formula I (X4 = CHOH) can be converted into the corresponding alkyl or acyl derivatives of the formula I (X4 = CHOR(30)) by alkylation or acylation with the compound of the formula L-R(30), where L has the above meaning , and R(30) also has the above meaning with the exception of hydrogen. Furthermore, for example, the hydroxyl group can be removed with a water splitting agent, so that a compound of formula I is obtained in which R(5) and R(11) together form one bond.

In all procedures, in certain stages of reactions, functional groups in the molecule can be temporarily protected. Such procedures with protecting groups are known to those skilled in the art. The choice of protective groups that may come into consideration and the procedures for their introduction and removal are described in the literature and can be easily adapted to individual cases if necessary.

The bicyclic precursors required for the above procedures are known from the literature or can be produced analogously by known procedures. Several methods for the production of these precursors are described, for example, in the following literature, the entire content of which is hereby considered an integral part of the proposed publication: J. Chem. Soc., Perkin Trans. 1, 1991, 2763; Eur. J. Med. Chem. 30(1995), 377; Ind. J. Chem. 9(1971), 809: J. Heterocyclic Chem. 26(1989), 1547.

It has already been said that the compounds of formula I have a surprisingly strong and specific blocking (closing) effect on K+-channels, which open with cyclic adenosine mono-phosphate (cAMP) and are fundamentally different from the well-known K+(ATK)-channels, and that they are very similar to the K+(cAMP)-channels identified in colon tissue, and may even be identical to the Iks-channels identified in cardiac muscle. The compounds according to the invention could be shown to have a strong blocking effect on Ix-channels in guinea pig cardiomyocytes as well as on Ix-channels expressed in xenopus oocytes. Because of this blocking of K+(cAMP)-channels, i.e. Ix-channels, the compounds according to the invention develop a pharmacological action of high therapeutic utility in the living organism and are extremely suitable as active substances of drugs for the therapy and prophylaxis of various types of diseases.

Thus, the compounds according to the invention of formula I stand out as a new class of active substances, strong inhibitors of increased gastric acid secretion. The compounds of the formula I are therefore valuable active substances of drugs for the therapy and prophylaxis of ulcers on the stomach and in the intestinal area, for example dudema. Due to their strong action in terms of inhibiting the secretion of gastric juice, they are therefore suitable as excellent agents for the therapy and prophylaxis of reflux esophagitis.

The compounds according to the invention of the formula I are also characterized by antidiarrheal activity and are therefore suitable as active substances of drugs for the therapy and prophylaxis of diarrheal diseases.

The compounds according to the invention of the formula I are also suitable as active substances of drugs for the therapy and prophylaxis of diseases of the cardiac circulation. They can be used especially for the therapy and prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, primarily for cardiac disorders that may occur due to prolongation of the action potential. They can be used for the therapy and prophylaxis of atrial fibrillation (atrial flutter) and atrial flutter (atrial flutter), as well as for the therapy and prophylaxis of reentry arrhythmias, and for the prevention of sudden cardiac death due to ventricular flutter.

Although there are numerous substances on the market that act as antiarrhythmics, there is still no compound that is truly satisfactory in terms of efficacy, scope of application and side effect profile, so there is a further need for the development of better antiarrhythmics. The action of numerous known class III antiarrhythmics is based on increasing the myocardial refract time by prolonging the duration of the action potential. This is mainly determined by measuring the repolarizing K+-current, which flows out of the cells via different K+-channels. The so-called "delayed rectifier" IK is of particular importance, of which there are two types, one quickly activating IKr and one slowly activating Iks. Most of the known class III antiarrhythmics block mainly or exclusively IKr (eg dofetilide, d-sotalol). It has been shown, however, that these compounds have an increased proarrhythmic risk at very low or normal heart rates, with arrhythmias designated as "Torsades de pointes" being especially observed (D.M. Roden: "Current Status of Class III Antiarrhythmic Drug Therapy" ; Am. J. Cardiol. 72(1993), 44B-49B). At higher heart rates, i.e. contrary to β-receptor stimulation, the action of the IKr-blocker that prolongs the action potential is clearly reduced, which means that under these conditions IKs contribute more strongly to repolarization. For these reasons, substances according to the invention, which act as Iks-blockers, have significant advantages compared to known Ikr-blockers. Meanwhile, it has also been described that there is a correlation between the inhibitory effect on Ix-channels and the ligature of life-threatening cardiac arrhythmias, which can be caused, for example, by β-adrenergic hyperstimulation (eg T.J. Colatsky, C.H. Follmer and C.F. Starmer; "Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias"; Circulation 82(1990), 2235-2242; A.E. Busch, K. Malloy, W.J. Groh, M.D. Varnum, J.P. Adelman and J. Maylie; " The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels in xenopus oocytes and IKs in guinea pig cardiac myocytes"; Biochem. Biophys. Res. Commun. 202 (1994), 265-270).

Furthermore, compounds I contribute to a clear improvement of heart failure, especially congestive heart failure, primarily in combination with active substances that promote contraction (positively inotropic), for example phosphodiesterase inhibitors.

Despite the therapeutically useful benefits that can be achieved by blocking Iks, only very few compounds have been described that inhibit this subtype of "delated rectifiers". The substance acimilide, which is still under development, does indeed show a blocking effect on Iks, but it predominantly blocks Ikr (selectivity 1:10). In WO-A-95/14470 the subject of patent protection is the use of benzodiazepines as a selective blocker of Iks. Further Iks-blockers are described in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating IsK channels by chromanols..." and Pflügers Arch.-Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon, acting by reduction of cAMP-activated K+ conductance". However, the strength of the compounds mentioned there is clearly lower than that of the compounds of formula I according to the invention.

The compounds of formula I according to the invention and their physiologically tolerable salts can be used for animals, primarily for mammals, and especially for humans as medicine by themselves, or in mutual mixtures or in the form of pharmaceutical preparations. The subject of the proposed invention are also compounds of formula I and their physiologically tolerable salts for use as medicine, their use in the therapy and prophylaxis of the mentioned diseases and their use for the production of such medicines and medicines with a blocking effect on K+-channels. The subject of the proposed invention is furthermore pharmaceutical preparations which, as an active ingredient, contain an effective dose of at least one compound of formula I and/or its physiologically tolerable salt in addition to the usual pharmaceutical flawless carriers and excipients. Pharmaceutical preparations normally contain 0.1 to 90 weight percent of the compound of formula I and/or its physiologically tolerable salts. The production of pharmaceutical preparations can be carried out in a manner known per se. For this purpose, the compound of formula I and/or its physiologically tolerable salts, together with one or more solid or liquid carriers and/or auxiliary substances and optionally in combination with other active substances of the drugs, is brought into a form suitable for administration, i.e. a dosage form which can then be used as medicine in human or veterinary medicine.

The drug containing the compound according to the invention of formula I and/or its salt can be administered orally, parenterally, for example intravenously, reactively, by inhalation or topically, whereby the preferred application depends on the individual case, for example the relevant manifestation of the disease being treated.

Excipients, suitable for the desired drug formulation, can be selected by the expert on the basis of professional knowledge. In addition to solvents, gel forming agents, bases for suppositories, excipients for tablets and other carriers of active substances, for example antioxidants, dispersing agents, emulsifiers, antifoaming agents, flavor correctors, preservatives, agents to improve dissolution, can be used. agents for achieving a depot effect, buffers or dyes.

To achieve a useful therapeutic effect, the compounds of formula I can also be combined with other active substances. Thus, combinations with substances that are active in the cardiac circulation are possible for the treatment of diseases of the cardiac circulation. As such, for diseases of the cardiac circulation, other antiarrhythmics come into consideration as useful substances for combinations, such as class I, class II or class III antiarrhythmics, such as IKr-channel blockers, e.g. dofetilide, or further substances that lower blood pressure, such as ACE-inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K+-channel activators, as alpha- and beta-receptor blockers, but also compounds with sympathomimetic and adrenergic effects, as well as Na+/H+-exchange inhibitors, calcium channel antagonists , phosphodiesterase inhibitors and other substances with a positive inotropic effect, such as digitalis glycosides or diuretics. Combinations with substances that have an antibiotic effect and with anti-ulcer agents, for example with H2-antagonists (eg ranitidine, cimetidine, famotidine, etc.), are also useful, especially when used to treat diseases of the stomach and intestines.

For the oral form of administration, the active compounds of the formula are mixed with suitable additional substances such as carriers, stabilizers or inert diluents and are then brought into a form suitable for administration, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions, by usual methods. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, the preparation can be made both as a dry and as a wet granulate. Suitable oil carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or liver oil. suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or their mixtures. Further auxiliary substances also for other forms of application are, for example, polyethylene glycols and polypropylene glycols.

For subcutaneous or intravenous application, the active compounds are translated into a solution, suspension or emulsion with the usual substances, such as agents for improving dissolution, emulsifiers or other auxiliary substances. The compounds of formula I and their physiologically tolerable salts can also be lyophilized and the obtained lyophilizates can be used, for example, for the preparation of injection or infusion preparations. Suitable solvents include, for example, water, physiological saline or alcohols, such as ethanol, propanol, glycerine, and in addition also sugar solutions, such as glucose solutions or mannitol solutions, or also mixtures of the various mentioned solvents.

Suitable pharmaceutical formulations for administration in aerosol or spray form are, for example, solutions, suspensions or emulsions of the active substance of formula I or its physiologically tolerable salts in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or in a mixture of such solvents. If necessary, the formulation may also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, as well as propellant gas. Such a preparation usually contains an active substance in a concentration of about 0.1 to 10, especially from about 0.3 to 3 wt. %.

The dosage of a given active substance of formula I, or its physiologically tolerable salt, depends on the individual case and is adjusted as usual for optimal effect under the circumstances of the case in question. Thus, the dosage depends, of course, on the frequency of administration and on the strength and duration of action of the respective compound used for therapy or prophylaxis, but also on the type and severity of the treated disease, as well as on the type, age and weight, and on the individual reaction of the treated human or animal. A typical daily dose of a compound of formula I for a patient weighing approximately 75 kg is from 0.001 mg/kg body weight to 100 mg/kg body weight, preferably from 0.01 mg/kg body weight to 20 mg/kg body weight. The dose can be given as a single dose or divided into several, eg two, three or four individual doses. Especially in the treatment of acute cases of heart rhythm disorders, for example in the intensive care unit, it can be useful by parenteral administration by injection or infusion, for example by continuous intravenous infusion.

Compounds of formula I and their physiologically tolerable salts selectively inhibit K+(cAMP)-channels or Iks-channels. Because of this property, in addition to being the active substance of medicines in human and veterinary medicine, they can also be used as a scientific tool or as an auxiliary tool for biochemical research, in which the effect on potassium channels is observed, and for diagnostic purposes, e.g. in diagnostics in vitro on cell or tissue samples. As mentioned above, they can also be used as intermediates for the production of further active medicinal substances.

Experimental part

List of abbreviations

DMA N,N-dimethylacetamide

DMSO dimethylsulfoxide

EE ethyl ester of acetic acid

Fp melting point (If not stated otherwise, the melting point refers to the unpurified raw product; the melting points of the respective pure substances may therefore be significantly higher.)

NBS N-bromosuccinimide

RT room temperature

THF tetrahydrofuran

Example 1

3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene

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a) 5 g (28 mmol) of 8-fluoro-1-benzosuberone and 2.1 g (31 mmol) of hydroxylamine hydrochloride in 20 ml of ethanol and 20 ml of pyridine are heated for 5 hours under reflux. The solvent is distilled off on a rotary evaporator and the residue is mixed with water, with adjust to pH 2 with hydrochloric acid and mix until the first oily product crystallizes. 5.1 g of 8-fluoro-1-benzosuberonoxime (melting point 97-103ºC) is obtained, which is reduced to 3-fluoro-5-amino-6 by hydrogenation in methanol under normal pressure and at room temperature with Raney nickel as a catalyst. 7,8,9-tetrahydro-5H-benzocycloheptene. Yield: 4.3 g; melting point of hydrochloride 212-216ºC.

b) To a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene and 1.5 g (60 mmol) of triethylamine in 40 ml of THF while cooling with ice, 2.3 g (18 mmol) of ethanesulfonic acid chloride are added dropwise. It is allowed to come to room temperature, stirred overnight and the solvent is distilled off under vacuum. The residue is mixed with water and then the excreted product is suctioned off. 2.9 g of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene are obtained. Melting point 118-121ºC.

Example 2

3-fluoro-5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene

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A solution of 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonyl- amino)-6,7,8,9-tetrahydro-5H-benzocycloheptene (Example 1) in 10 ml of DMA. After stirring for 3 hours at room temperature, 0.63 g (4.5 mmol) of methyl iodide was added dropwise and allowed to continue stirring overnight at room temperature. The solvent is distilled off and the residue is mixed with water and extracted with EE. The organic phase is dried over sodium sulfate and concentrated in vacuo. 0.64 g of 3-fluoro-5-(N-ethyl-sulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene is obtained.

Example 3

3-fluoro-5-(N-ethylsulfonyl-N-butylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene

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Analogously to example 2, from 0.12 g (4.1 mmol) of an 80% sodium hydride suspension, 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9- tetrahydro-5H-benzocycloheptene and 0.82 g (4.5 mmol) of butyl iodide, 0.88 g of 3-fluoro-5-(N-ethylsulfonyl-N-butylamino)-6,7,8,9- of tetra-hydro-5H-benzocycloheptene.

Example 4

trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol

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a) 2,3-dihydro-7-nitro-1-benzoxepine

To a suspension of 50 g of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1, 1991 2763) in 345 ml of methanol at 0ºC with vigorous stirring is added in portions 10.2 g of sodium borate. After 30 minutes, the reaction mixture is poured over water, the solid substance is sucked off and 43 g of 7-nitro-2,3,4,5-tetrahydro-1-benzoxepin-5-ol is obtained. This is heated with 1 g of p-toluenesulfonic acid in 520 ml of toluene for 2 hours on a water separator. When it cools down, the aqueous phase is washed with a sodium bicarbonate solution and with a salt solution. After drying over sodium sulfate and concentration, 38.8 g of 2,3-dihydro-7-nitro-1-benzoxepine is obtained. Melting point 98-100ºC.

b) 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

72.3 g of NBS was added to a solution of 38.8 g of 2,3-dihydro-7-nitro-1-benzoxepine in 780 ml of DMSO and 78 ml of water under ice cooling, whereby the temperature rose to 30ºC. After 90 minutes of stirring at room temperature, the reaction mixture is poured into 5 l of ice water, stirred for 1 hour, the crystalline precipitate is suctioned off and 60 g of bromohydrin is obtained. A solution of bromohydrin in 465 ml of methanol is added dropwise at room temperature to a solution of 5.1 g of sodium in 400 ml of methanol. It is stirred for 1 hour and the separated precipitate is sucked off and washed with water. After drying, 37 g of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine are obtained. Melting point 123-125ºC.

c) N-methyl-N-trimethylsilyl-ethanesulfonamide

A mixture of 33 g of N-methyl-ethanesulfonamide, 101 g of hexamethyldisilazane and, on the tip of a knife, ammonium chloride in argon is first heated for 2 hours at 100ºC and then heated for another 1 hour at 130ºC. Distillation of the reaction mixture in vacuum at a boiling point of 118-121ºC/10 Torr yields 42 g of N-methyl-N-trimethylsilyl-ethanesulfonamide.

d) trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol

To a mixture of 6 g of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepin and 9.5 g of N-methyl-N-trimethylsilyl-ethane-sulfonamide is added with stirring 2 g of tetrabutylammonium fluoride. It is then heated for 3 hours at 65ºC, stirred overnight at room temperature and the reaction mixture is poured into an ammonium chloride solution. It is extracted several times with EE, the organic phase is washed with water and dried over sodium sulfate. After concentration and recrystallization of the solid residue from isopropanol, 7.1 g of trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol is obtained. Melting point 133-135ºC.

Example 5

trans-7-cyano-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol

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To a mixture of 4 g of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepine-7-carbonitrile (J. Chem. Soc., Perkin Trans. 1, 1991, 2763) and 7.0 g 1.5 g of tetrabutylammonium fluoride is added to N-methyl-N-trimethylsilyl-ethanesulfonamide with stirring. It is then heated for 3 hours at 60ºC, stirred overnight at room temperature and the reaction mixture is poured into an ammonium chloride solution. It is extracted several times with EE, the organic phase is washed with water and dried over sodium sulfate. After concentration and recrystallization of the solid residue from cyclohexane/EE (1:5), 3.2 g of trans-7-cyano-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1 -benzoxepin-4-ol. Melting point 142-144ºC.

Example 6

5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine

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a) A solution of 10.0 g of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1, 1991, 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine is heated for 5 hours under reflux. The solvent is distilled off on a rotary evaporator and the residue is mixed with water, with adjust to pH 2 with hydrochloric acid and mix for another 3 hours. After suction and drying of the excreted product, 10.2 g of 3,4-dihydro-1-benz-oxepin-5(2H)-one-oxime are obtained. Melting point 96-98ºC.

b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benz-oxepin-5(2H)-one-oxime in 15 ml of 1,2-dimethoxyethane (DME) at 0ºC in argon is added dropwise to a mixture of 4.5 g (23.7 mmol) titanium tetrachloride and 1.79 g (47.4 mmol) sodium borate in 50 ml DME over 20 minutes. After mixing for 2 days at room temperature, 100 ml of water is added drop by drop and with conc. make it alkaline with ammonia solution. After suctioning off the precipitate, the filtrate is extracted three times with EE. After washing with a solution of common salt, drying over magnesium sulfate and concentration, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine is obtained.

c) To a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF with cooling 0.86 g (6.7 mmol) of ethanesulfonic acid chloride is added dropwise with ice. It is allowed to come to room temperature, stirred overnight and the solvent is distilled off under vacuum. The residue is mixed with water and the excreted product is suctioned off. 1.1 g of 5-ethyl-sulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 109-111ºC.

d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2 is added dropwise to a suspension of 0.16 g (5.4 mmol) of 80% sodium hydride in 10 ml of THF under a nitrogen atmosphere. of 3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF. It is stirred for 3 hours at room temperature and then 1.6 g (11 mmol) of methyl iodide is added dropwise and left to continue stirring overnight at room temperature. The solvent is distilled off and the residue is mixed with water and extracted with EE. The organic phase is dried over sodium sulfate and concentrated in vacuo. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 122-124ºC.

Example 7

5-(N-butyl-N-ethylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine

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8.3 g of 5-(N-butyl-N- ethylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine as a viscous oil, which crystallizes after a long time. Melting point 62-65ºC.

Example 8

5-(N-methyl-N-methylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine

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a) A solution of 2.0 g (12.2 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (example 6b) and 3.5 g (36.6 mmol) of triethylamine in 40 1.54 g (13.4 mmol) of methanesulfonic acid chloride are added dropwise to ml of THF with ice cooling. It is allowed to come to room temperature, stirred overnight, mixed with 50 ml of water and the THF is distilled off under vacuum. The residue is diluted with a further 50 ml of water, stirred for 3 hours and the secreted product is suctioned off. After drying in a vacuum, 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 105-106ºC.

b) A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a suspension of 0.23 g (6.2 mmol) of 80% sodium hydride in 10 ml of THF. It is stirred for 2 hours at room temperature and then 0.94 g (6.7 mmol) of iodomethane is added and stirring is continued overnight at room temperature. The solvent is distilled off under vacuum, the residue is taken up in EE, washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated. After recrystallization of the product from isopropanol, 0.5 g of 5-(N-methyl-N-methylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 143-145ºC.

Example 9

5-(N-butyl-N-methylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine

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1.0 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine (Example 8a) was chemically converted analogously to Example 11 with sodium hydride and iodobutane in DMF. After recrystallization of the crude product (1.0 g) from isopropanol, 0.4 g of 5-(N-butyl-N-methylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 78-79ºC.

Example 10

7-chloro-9-methyl-5-(N-ethylsulfonyl-N-methyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine

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a) A mixture of 90 g of 4-(4-chloro-2-methylphenoxy)butyric acid (Aldrich) and 1000 g of polyphosphoric acid is stirred for 4.5 hours at 85ºC. The reaction mixture is then poured into 5 l of water, stirred for another hour and extracted with ether. The combined organic phases are washed several times with soda solution and water, dried over magnesium sulfate and centrifuged. The dark residue is taken up again in ether and boiled several times with activated carbon and silica gel, and filtered, until only a faint color is obtained. After concentration, 48.7 g of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one is obtained; melting point: 56-58ºC.

b) 3.0 g of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one, 50 ml of anhydrous methanol, 10.9 g of ammonium acetate and 0.63 g of sodium borohydride are mixed 5 hours at 60ºC and 2 days at room temperature. Then, the reaction mixture is acidified with hydrochloric acid and concentrated on a rotary evaporator. The residue is taken up in water, made alkaline with ammonia solution and extracted with ethyl acetate. After drying and concentration, the product is purified by chromatography on silica gel with acetic ester/methanol 9:1 and 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1- benzoxepine.

c) A solution of 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine and 2.4 g of triethylamine in 30 ml of THF with ice-cooling drop by drop with 0.86 g of ethane-sulfonic acid chloride. It is allowed to come to room temperature, it is stirred overnight and the solvent is distilled off under vacuum. The residue is diluted with water and the secreted product is sucked off and dried in a vacuum. 1.6 g of 7-chloro-9-methyl-5-(N-ethylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine is obtained; melting point: 144-145ºC.

d) A solution of 0.6 g (2.0 mmol) 7-chloro-9-methyl is added dropwise to a suspension of 0.1 g (2.7 mmol) of 80% sodium hydride in 5 ml of THF in nitrogen of -5-(N-ethylsulfonyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine in 8 ml of THF. It is stirred for 1 hour at room temperature and then 0.41 g (2.9 mmol) of methyl iodide is added dropwise and left to continue stirring overnight at room temperature. The solvent is distilled off and the residue is mixed with water and extracted with EE. After washing the organic phase with with hydrochloric acid and water, and drying over magnesium sulfate, it is concentrated in a vacuum and the crude product is recrystallized from methylene chloride. 0.4 g of 7-chloro-9-methyl-5-(N-ethylsulfonyl-N-methyl-amino)-2,3,4,5-tetrahydro-1-benzoxepine is obtained; melting point 141-143ºC

1H-NMR (CDCl 3 ): δ (ppm) = 1.35 (3H); 1.9-2.2 (4H); 2.2 (3H); 3.05 (2H); 3.7 (1H); 4.2 (1H); 5.15 (1H), 7.1 (2H).

Example 11

5-(N-butyl-N-ethylsulfonyl-amino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine

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A solution of 0.8 g (2.6 mmol) 7-chloro-9-methyl-5 -(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 ml of DMF. It is stirred for 30 minutes at room temperature and then 0.68 g (3.7 mmol) of butyl iodide is added dropwise and allowed to continue stirring overnight at room temperature. The solvent is distilled off and the residue is mixed with water and extracted with EE. After washing the organic phase with with hydrochloric acid and water, and after drying over magnesium sulfate, it thickens in a vacuum. 0.9 g of 5-(N-butyl-N-ethylsulfonyl-amino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine is obtained; melting point 83-87ºC.

Example 12

5-(N-butyl-N-methylsulfonyl-amino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine

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0.6 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine (Example 10b) is chemically converted analogously to Example 10c with methanesulfonic acid chloride. 0.6 g of 7-chloro-9-methyl-5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine is obtained; melting point 154-156ºC. Then, by alkylation with butyl iodide, analogous to example 11, 0.6 g of 5-(N-butyl-N-methylsulfonyl-amino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1- benzoxepine; melting point: 106-110ºC.

Example 13

5-(N-butyl-N-methylsulfonyl-amino)-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine

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a) 10.0 g (61.7 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1, 1991, 2763) is introduced under ice cooling in 80 ml conc. sulfuric acid. Then 5.77 g (67.9 mmol) of sodium nitrite were added and stirred for 90 minutes at 0ºC. The reaction mixture is poured into 800 ml of ice water, the excreted product is sucked off, washed until neutral and dried in a vacuum. After recrystallization from isopropanol, 7 g of 3,4-dihydro-7-nitro-1-benz-oxepin-5(2H)-one was obtained, which was contaminated with 12% of the corresponding 7,9-dinitro compound. Melting point 112-116ºC.

b) 3.4 g (16.4 mmol) of 3,4-dihydro-7-nitro-1-benz-oxepin-5(2H)-one is mixed with 12.7 g (164 mmol) of ammonium acetate and 7, 2 g (115 mmol) of sodium cyanoborohydride in 55 ml of methanol for 3 hours at 60ºC. After the addition of 10 ml of water, the reaction mixture is concentrated in a vacuum and the residue is taken up in acetic ester and washed with dil. sodium lye. The phase in EE is extracted with div. with hydrochloric acid and the resulting phase in hydrochloric acid is made alkaline with sodium hydroxide solution and extracted with EE. After drying the extract in EE, 1.7 g of 5-amino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine was obtained.

c) From 1.6 g of 5-amino-7-nitro-2,3,4,5-tetrahydro-1-benz-oxepin, analogously to example 8a, 1.9 g of 5-methyl-sulfonylamino-7-nitro was obtained -2,3,4,5-tetrahydro-1-benzoxepine. Melting point 150-151ºC.

d) From 0.5 g of 5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine by chemical conversion with sodium hydride and iodobutane in DMF, analogously to example 11, 0.6 g was obtained 5-(N-butyl-N-methylsulfonyl-amino)-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine. Melting point 96-98ºC.

Example 14

7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one

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a) 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one can be obtained from 4-butoxyphenol by alkylation with ethyl ester of 4-bromobutyric acid, then by saponification and cyclization in the presence of polyphosphoric acid, as described in J. Heterocyclic Chem. 26, 1989, 1547 for the analogous 7-propoxy-3,4-dihydro-2H-1-benzoxepin-5-one.

b) From 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one by reductive amination with ammonium acetate and sodium cyanoborohydride followed by conversion with methanesulfonic acid chloride and finally alkylation with butyl iodide, as described in example 13b-d, 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one was obtained.

Pharmacological research

IsK-channels from human, rat and guinea pig are expressed in Xenopus oocytes. For this purpose, oocytes from Xenopus Laevis were first isolated and defolicured. RNA synthesized in vitro, which codes for IsK, was then injected into these oocytes. After 2-8 days of IsK-protein expression on oocytes, the IsK-current was measured using the voltage clamp method with two microelectrodes. As a rule, IsK channels were activated at -10 mV with voltage jumps lasting 15 s. The bath was washed with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl2 1.8 mM, MgCl2 1 mM, HEPES 5 mM (titrated with NaOH to pH 7.5). These experiments were carried out at room temperature. A Geneclamp amplifier (Axon Instruments, Foster City, USA) and a MacLab D/A converter and software (ADInstrumetns, Castle Hill, Australia) were used for data collection and analysis. Substances according to the invention were tested, where they were added to the bath solution with different concentrations. The effect of the substance was calculated as the percentage inhibition of the IsK-control current, which was obtained when no substance was added to the solution. To determine the IC50 inhibitory concentration for the substance in question, the data were then extrapolated using the Hill equation.

Literature:

A. E. Busch, H.-G. Kopp, S. Waldegger, I. Samarzija, H. Süßbrich, G. Raber, K. Kunzelmann, J.P. Ruppersberg and F. Lang: "Inhibition of both exogenously expressed IsK and endogenous K+ channels in Xenopus oocytes by isosorbide dinitrate"; J. Physiol. 491 (1995), 735-741;

T. Takumi, H. Ohkubo and S. Nakanishi: Cloning of membrane protein that induces a slow voltage-gated potassium current”; Science 242 (1989), 1042-1045; 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. Natl. Acad. USA 90 (1993), 11528-11532.

In the described manner, an IC50 value of 3.3 µmol/l was obtained for the compound from example 13.

Claims (20)

1. Compounds of formula I, [image] indicated by that X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)-, -NR(6)-, -CO- or -CR(1)R(7); R(1) and R(2) independently of each other represent hydrogen, CF3, C2F5, C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 a substituent selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; or R(1) and R(2) together form an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(6) is hydrogen or -CnH2n-R(8), whereby one CH2-group in the group CnH2n can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(9)- or -CONR(9)-; R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R(8) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazine -1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; X2 represents -CR(1)R(2)- or -CR(2)R(10)-; or X2 if X3 and X1 represent -CR(1)R(2)-, also represents -O-, -S-, -SO-, -SO2- or -NR(6)-, wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1; R(10) together with R(7) forms one bond; X 3 is -CR(1)R(2)-; or X3 if X2 and X4 represent -CR(1)R(2)-, also represents -O-, -S-, -SO-, -SO2- or -NR(6)-, wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1; X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)-, -CH(OR(30))- or -CR(2)R(11)-, wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1; R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms; R(11) together with R(5) forms one bond; Y1, Y2, Y3 and Y4 independently represent -CR(12)- or N, whereby at most 2 of the groups Y1, Y2, Y3 and Y4 can simultaneously be N; residues R(12) are independently hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4, or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms -atom, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, J , CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is zero, 1, 2, 3, 4, 5 or 6; R(13) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, -NR(15)R(16)-, -CONR(15)R(16 )-, -OR(30a), phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-; R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-; residues R(12) are defined independently of each other as Y1, Y2, Y3 and Y4; R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-, whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-; R(19) is hydrogen, methyl or ethyl; R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, CF3, C2F5 or C3F7; x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or R(18) and R(17) together form one bond, if x is not less than 3; or R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or R(3) together with R(4) represents an alkylene chain having 3, 4, 5, 6, 7 or 8 carbon atoms; wherein one CH2-group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO- or -SO2-; R(4) represents -CrH2r-R(20), whereby one CH2-group in the CrH2r group can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O -, -O-CO-, -S-, -SO-, -SO2-, -NR(21)- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R(20) represents hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with -N(benzyl)-; R(5) represents hydrogen or together with R(11) forms one bond; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 2. Compounds of formula I according to claim 1, characterized in that X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the meanings specified in claim 1, wherein, however, both residues R(3) and R(4) are other than hydrogen, in all their stereoisomeric forms and mixtures thereof in any proportions, and their physiologically tolerable salts. 3. Compounds of formula I according to claim 1 and/or 2, characterized in that X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)- or -NR(6)-; R(1) and R(2) independently of each other represent hydrogen, CF3, C2F5, C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 a substituent selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; or R(1) and R(2) together form an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(6) is hydrogen or -CnH2n-R(8), whereby one CH2-group in the group CnH2n can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(9)- or -CONR(9)-; R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; n is zero, 1, 2, 3, 4, 5, 6, 7 or 8; R(8) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl , pyridyl, thienyl, imidazolyl or phenyl, wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; X 2 represents -CR(1)R(2)-; wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X3 is -CR(1)R(2)-, wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)- or -CH(OR(30))-; wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1; R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms; R(11) together with R(5) forms one bond; Y1, Y2, Y3 and Y4 independently represent -CR(12)- or N, whereby at most 2 of the groups Y1, Y2, Y3 and Y4 can simultaneously be N; the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, cycloalkyl having 3, 4, 5 or 6 C-atoms, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is zero, 1, 2, 3, 4, 5 or 6; R(13) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(15)R(16)-, -CONR(15)R(16)-, -OR(30a) , phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-; R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-; residues R(12) are defined independently of each other as indicated by Y1, Y2, Y3 and Y4; R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-, whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-; R(19) is hydrogen, methyl or ethyl; R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 C-atoms, CF3, C2F5 or C3F7; x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or R(18) and R(17) together form one bond, if x is not less than 3; or R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or R(3) together with R(4) represents an alkylene chain having 3, 4, 5, 6, 7 or 8 carbon atoms; wherein one CH2-group of the alkylene chain can be replaced by -O-, -CO-, -S-, -SO- or -SO2-; R(4) represents -CrH2r-R(20)-, whereby one CH2-group in the group CrH2r can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(21)- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R(20) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with -N(benzyl)-; R(5) represents hydrogen or together with R(11) forms one bond; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 4. Compounds of formula I according to one or more claims 1 to 3, characterized in that X1 represents -O-, -S-, -SO-, -SO2-, -CR(1)R(2)- or -NR(6)-; R(1) and R(2) independently represent hydrogen, CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R(1) and R(2) together form an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms; R(6) is hydrogen or -CnH2n-R(8), whereby one CH2-group in the group CnH2n can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(9)- or -CONR(9)-; R(9) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; n is zero, 1, 2, 3, 4, 5, 6, 7 or 8; R(8) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl , imidazolyl or phenyl, wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; X 2 represents -CR(1)R(2)-; wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X3 is -CR(1)R(2)-, wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X4 represents -CR(1)R(2)-, -NR(6)-, -NR(11)- or -CH(OR(30))-; wherein the residues R(1), R(2) and R(6) are defined as specified in X1, but are independent of the meanings of the residues in X1; R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms; R(11) together with R(5) forms one bond; Y1, Y2, Y3 and Y4 independently represent -CR(12)-; the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, cycloalkyl having 3, 4, 5 or 6 C-atoms, CN, CF3, C2F5, C3F7, N3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is zero, 1, 2, 3, 4, 5 or 6; R(13) represents hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(15)R(16)-, -CONR(15)R(16)-, -OR(30a) , phenyl, thienyl or heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-; R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or Y1 and Y2 together with the sulfur atom and Y3 and Y4 represent the group -CR(12)-; residues R(12) are defined independently of each other as indicated by Y1, Y2, Y3 and Y4; R(3) represents R(17)-CxH2x-NR(18)- or R(17)-CxH2x-, whereby one CH2-group in the group CxH2x can be replaced by -O-, -CO-, -S-, -SO-, -SO2- or -NR(19)-; R(19) is hydrogen, methyl or ethyl; R(17) is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, C2F5 or C3F7; x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or R(18) and R(17) together form one bond, if x is not less than 3; or R(3) represents phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl , methylsulfonyl and methylsulfonylamino; or R(4) represents -CrH2r-R(20)-, whereby one CH2-group in the group CrH2r can be replaced by -O-, -CH=CH-, -C≡C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO2-, -NR(21)- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(20) represents hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4, 5 or 6 C-atoms, -NR(22)R(23), phenyl, thienyl or heterocycle containing nitrogen with 1, 2, 3, 4, 5, 6, 7 or 8, or 9 C-atoms, wherein phenyl, thienyl and nitrogen-containing heterocycle are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(22) and R(23) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(22) and R(23) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with -N(benzyl)-; R(5) represents hydrogen or together with R(11) forms one bond; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 5. Compounds of formula I according to one or more claims 1 to 4, characterized in that X1 represents -O- or -CR(1)R(2)-; R(1) and R(2) independently represent hydrogen, CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; X 2 represents -CR(1)R(2)-; wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X3 is -CR(1)R(2)-, wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; X4 represents -CR(1)R(2)- or -CH(OR(30))-; wherein the residues R(1) and R(2) are defined as specified in X1, but are independent of the meanings of the residues in X1; R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms; Y1, Y2, Y3 and Y4 independently represent -CR(12)-; the residues R(12) independently represent hydrogen, F, Cl, Br, J, alkyl having 1, 2, 3, 4 or 5 C-atoms, CN, CF3, NO2, -Z-CmH2m-R(13) or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is zero, 1, 2 or 3; R(13) represents hydrogen, CF3, -NR(15)R(16)-, -CONR(15)R(16)-, -OR(30a), phenyl, thienyl or a heterocycle containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, thienyl and heterocycle containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(15) and R(16) together form a chain having 4 or 5 methylene groups, one of which CH2-group can be substituted with -O-, -S-, -NH-, -N(CH3)- or with - N(benzyl)-; R(30a) is hydrogen, alkyl having 1, 2 or 3 C-atoms or acyl having 1, 2, 3 or 4 C-atoms; or R(3) represents R(17)-CxH2x-, R(17) is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms or CF3; x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(4) represents -CrH2r-R(20)-, whereby one CH2-group in the group CrH2r can be replaced by -O-, -CO-, -CO-O-, -O-CO-, -NR(21)- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R(20) represents methyl, CF3 or cycloalkyl having 3, 4, 5 or 6 carbon atoms; R(5) represents hydrogen; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 6. Compounds of formula I according to one or more claims 1 to 5, characterized in that X1 represents -O- or -CH2; X2 represents -CR(1)R(2)-, R(1) and R(2) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; X 3 is -CH 2 - or -C(CH 3 ) 2 ; X 4 is -CH 2 - or -CHOH-; Y1, Y2, Y3 and Y4 independently represent -CR(12)-; residues R(12) independently of each other represent hydrogen, F, Cl, Br, alkyl having 1, 2 or 3 C-atoms, CN, CF3, NO2, -Z-CmH2m-R(13); Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)-, -NR(14)- or -CONR (14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is zero, 1, 2 or 3; R(13) represents hydrogen, CF3, -NR(15)R(16)-, phenyl, piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl or imidazolyl; R(15) and R(16) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(3) represents R(17)-CxH2x-, R(17) is methyl; x is zero, 1, 2 or 3; R(4) represents -CrH2r-R(20), whereby one CH2-group in the group CrH2r can be replaced by -O-, -CO-, -CO-O-, -O-CO-, -NR(21)- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5 or 6; R(20) represents methyl, CF3 or pyridyl; R(5) represents hydrogen; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 7. Compounds of formula I according to one or more claims 1 to 5, characterized in that X1 represents -O-; X2 represents -CR(1)R(2)-, R(1) and R(2) independently represent hydrogen or alkyl having 1, 2 or 3 carbon atoms; X 3 is -CH 2 - or -C(CH 3 ) 2 ; X 4 is -CH 2 -; Y1 is CH; Y 2 is CH; Y 4 is CH; Y3 is -CR(12)-; R(12) represents F, Cl, Br, alkyl having 1, 2 or 3 carbon atoms, CN, CF3, NO2, -Z-CmH2m-R(13); Z represents -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -SO2NR(14)- or -CONR(14)-; R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; m is 1, 2 or 3; R(13) represents hydrogen, CF3, pyridyl or phenyl; R(3) represents R(17)-CxH2x-, R(17) is methyl; x is 0, 1 or 2; R(4) represents -CrH2r-R(20), whereby one CH2-group in the group CrH2r can be replaced by -O-, -CO-O-, -O-CO- or -CONR(21)-; R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is zero, 1, 2, 3, 4, 5 or 6; R(20) represents methyl, CF3; R(5) represents hydrogen; in all their stereoisomeric forms and their mixtures in any proportions, and their physiologically tolerable salts. 8. Compounds of formula I according to one or more claims 1 to 7 and their physiologically tolerable salts, indicated by the fact that they are used as medicine. 9. Pharmaceutical preparation, characterized in that it contains an effective amount of at least one compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, together with a pharmaceutically acceptable carrier and additional substances and, if necessary, one or more other pharmaceutical active substances. 10. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug, which acts by blocking K+-channels, for the therapy and prophylaxis of K+-mediated diseases channels 11. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for inhibiting the secretion of gastric acid. 12. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for the therapy or prophylaxis of ulcers on the stomach or in the intestinal area. 13. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a medicine for the therapy or prophylaxis of reflux esophagitis. 14. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for therapy or prophylaxis of diarrheal diseases. 15. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for therapy or prophylaxis of all types of arrhythmias, including ventricular and supraventricular arrhythmias. 16. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for therapy or prophylaxis of heart rhythm disorders that may occur due to prolongation of the action potential. 17. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for the therapy or prophylaxis of atrial fibrillation or atrial flutter. 18. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for the therapy or prophylaxis of reentry arrhythmias or for the prevention of sudden cardiac death due to ventricular fibrillation. 19. Use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, characterized in that it is used for the production of a drug for the treatment of heart failure. 20. The use of the compound of formula I according to one or more claims 1 to 7 and/or its physiologically tolerable salt, indicated by the fact that it is used for the inhibition of increased secretion of gastric acid, for the therapy or prophylaxis of ulcers on the stomach or in the intestinal area, reflux esophagitis, diseases with diarrhea, for the therapy or prophylaxis of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial flutter and reentry arrhythmias, or for the prevention of sudden cardiac death due to ventricular flutter.