SK23998A3 - Sulfonamido substituted anellated seven-membered ring compounds, their use and pharmaceutical compounds containing same - Google Patents

Abstract

Benzoxepine and benzocycloheptane derivatives of formula (I), their stereoisomers and salts are new. X1 = O, S, SO, SO2, CR1R2, NR6, CO or CR1R7; R1, R2 = H, CF3, C2F5, C3F7, 1-6C alkyl or phenyl (optionally substituted by 1 or 2 of halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me; or R1+R2 = 2-10C alkylene; R6 = H or CnH2nR8 (with one CH2 group optionally replaced by O, CH=CH, C IDENTICAL C, CO, COO, OCO, S, SO, SO2, NR9 or CONR9; R9 = H or 1-4C alkyl; n = 0-8; R8 = H, CF3, C2F5, C3F7, 3-8C cycloalkyl, NMe2, NEt2, piperidino, pyrrolidino, morpholino, 4-methyl-1-piperazinyl or pyridyl, thienyl, imidazolyl or phenyl (all optionally substituted by 1 or 2 halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me); X2 = CR1R2 or CR2R10; or X2 = O, S, SO, SO2 or NR6 if X3 and X1 are CR1R2; R10+R7 = bond; X3 = CR1R2; or X3 = O, S, SO, SO2 or NR6 if X2 and X4 are CR1R2; X4 = CR1R2, NR6, NR11, CH(OR30) or CR2R11; R30 = H, 1-3C alkyl or 1-4C acyl; R11+R5 = bond; Y1-Y4 = CR12 or N with no more than two being N; R12 = H, halo, 1-5C alkyl, 3-8C cycloalkyl, CN, CF3, C2F5, C3F7, N3, NO2, ZCmH2mR13 or phenyl (optionally substituted by 1 or 2 halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me); Z = O, CO, COO, OCO, S, SO, SO2, SO2NR14, NR14 or CONR14; R14 = H or 1-3C alkyl; m = 0-6; R13 = H, CF3, C2F5, C3F7, 3-8C cycloalkyl, NR15R16, CONR15R16, OR30a or phenyl, thienyl or 1-9C N-containing heterocyclyl (all optionally substituted by 1 or 2 halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me); R15, R16 = H or 1-3C alkyl; or R15+R16 = 4-5C methylene (with one carbon optionally replaced by O, S, NH, NMe or N(benzyl)); R30a = H, 1-3C alkyl or 1-4C acyl; or Y1+Y2 = S and Y3, Y4 = CR12; R3 = NR18CxH2xR17 or CxH2xR17 (with one CH2 group optionally replaced by O, CO, S, SO, SO2 or NR19); R19 = H, Me or Et; R17 = H, Me, 3-8C cycloalkyl, CF3, C2F5 or C3F7; x = 0-10; R18 = H or 1-8C alkyl; or R18+R17 = bond if x = 3-10; or R3 = phenyl (optionally substituted by 1 or 2 halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me); or R3+R4 = 3-8C alkylene (with one CH2 optionally replaced by O, CO, S, SO or SO2); R4 = CrH2rR20 (with one CH2 group optionally replaced by O, CH=CH, C IDENTICAL C, CO, COO, OCO, S, SO, SO2, NR21 or CONR21); R21 = H or 1-3C alkyl; r = 0-20; R20 = H, CF3, C2F5, C3F7, 3-8C cycloalkyl, NR22R23 or phenyl, thienyl or 1-9C N-containing heterocyclyl (all optionally substituted by 1 or 2 halo, CF3, NO2, CN, NH2, OH, Me, Et, OMe, NMe2, SO2NH2, SO2Me and NHSO2Me); R22, R23 = H or 1-3C alkyl; or R22+R23 = 4-5C methylene (with one carbon optionally replaced by O, S, NH, NMe or N(benzyl)); and R5 = H; or R5+R11 = bond.

Description

Sulfonamide-substituted fused seven-membered compounds, their use and pharmaceutical compositions thereof

I contain ú

Technical field

The invention relates to compounds of formula I,

R?

(d) where 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 meaning given below, their preparation and use mainly in medicaments. The compounds cause an open channel or cAMP on cyclic adenosine monophosphate (cAMP). _IKs channel identified and are suitable team as pharmaceutical active compounds e.g. for the prophylaxis and treatment of cardiovascular diseases, particularly arrhythmias, for the treatment of gastric and intestinal ulcers, or for the treatment of diarrhea.

BACKGROUND OF THE INVENTION

In recent years, chemistry of 4-acylaminochroman derivatives has been studied extensively. The best test results were achieved by a representative of this class, Cromakalim of formula A, an example

homologue is compound of formula B (J. Chem. 'Soc. Perkin Trans. 1 1991, 2763). O.0 N ^u Ck N ^U ', OH ¥ T i l O ^ CH

A

B

For Cromakalime and other similar derivatives

4-acylaminochroman is involved and compounds that relax smooth muscle so that they are used to lower blood pressure by relieving vascular muscle and to treat asthma by relieving smooth muscle of the airways.

All of these agents act on smooth muscle cell cells and thus lead to levels of e.g. to open certain ATP-sensitive channels.

K ⁺ ion-induced rise in negative charge in the cell (hyperpolarization) causes an increase in intracellular Ca ²⁺ concentration via secondary mechanisms and thereby counteractivates the cell, which leads e.g. muscle contraction.

Furthermore, the compounds of the formula I according to the invention differ structurally from these acylamino derivatives by replacing the acylamino group with a sulfonylamino group. While Cromakalim (Formula A) and the homologue of Formula B and analogous acylamino derivatives act as openers for ATP-sensitive K ⁺ channels, however, compounds of Formula I with a sulfonylamino structure do not show any opening effect on this K ⁺ (ATP) channel however, they have a surprisingly potent and specifically blocking (closure) effect on the K ⁺ channel which has been opened by cyclic adenosine monophosphate (cAMP) and which is substantially different from said K ⁺ (ATP) channel. A more recent study shows that this K ⁺ (cAMP) channel found in the colon is very similar, possibly even identical, to the I _Ks channel found in the heart muscle.

In fact, there may have been a strong blocking effect on. The _Ks- channel in experiments in guinea pig cardiomyocytes as well as oocytes in the Xenopus species, for the compounds according to the present invention of formula I and for

I _Ks ^- channel.

As a result of this blocking of the K ⁺ (cAMP) -channel respectively.

The _Ks- channels induce compounds of the present invention in living organisms to exert a pharmacological effect of higher therapeutic value.

In addition to the above-mentioned Cromakalim derivatives, respectively. Acylaminochroman also discloses in the literature compounds having a 4-sulfonylaminochroman structure, which, however, clearly differ in structure and biological activity from the compounds of formula I in accordance with the present invention. EP-A-315 009 discloses chromate derivatives having a 4-phenylsulfonylamino structure having antithrombotic and antiallergic properties. In EP-A-389 861 and EP-A-370 901, 3-hydroxychroman derivatives with a 4-sulfonylamino group are described which activate the K '(ATP) -channel, respectively. acting through the CNS. Other 4-sulfonylaminochroman derivatives are described in Bioorg. Med. Chem. Lett. 4 (1994), 769-773. &Quot; N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburyde insensitive muscle relaxants to potent smooth muscle contractors.

The present invention relates to compounds of formula I,

R ³ o = s = o

(I) in which:

X ¹ is -O-, -S-, -SO-, -SO ₂ -, -CR ² -, -NR ⁶ -, -CO-, or -CR ¹ R '-, i 2 _z

R * and R are independently hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, di4 methylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, 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 c is hydrogen or -C _n H _{2 n} -R ⁸ 7 wherein one methylene group C _n H 2 _n can be replaced by -O-, -CH = CH-, -C = C-, -CO- , -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -NR ⁹ -, or -CONR ⁹ -, q

R 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 is an atom H, trifluoromethyl, pentafluoro- ethyl group, heptafluoropropyl group, cyclo alkyl group containing 3, 4, 5, 6, 7 or 8 carbon

carbon, dimethylamino, diethylamino, 1-pipe. Ridyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein the pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted 1. or 2 · substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino,

X ² is -CR ^X R ² - or -CR ² R ¹⁰ · 1 · · or, if X ³ and X ¹ is -CR 1 R ² -, X ² is also -O-, -S-, -SO ₂ -, -SO ₂ - or NR ⁵ -, wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ but are independent of the radicals X ¹ ,

R ¹⁰ together with R ^{7 represents a} bond,

I

X ³ is -CR ¹ R ² -, or when X ² and X ⁴ is -CR ¹ R ² -, X ^{3 is} also -O-, -S-, -SO-, -SO ₂ or NR ⁶ -, wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ , but are independent of the radicals X ¹ , -CR ¹ R ² -, -NR ⁶ -, -NR ¹¹ - , -CH (oR ³⁰⁾ - or -CR ² R ^U, wherein the radicals R ^1, R ² and R ⁶ are as defined for ^X1, but are independent of the radicals X ^1,

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 represents a} bond,

Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² - or a nitrogen atom, wherein at least 2 of Y ¹ , Y ² , Y ³ and Y ⁴ may also be nitrogen atoms,

R ¹² is independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms cyano, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, azide, nitro, -ZC _m H _2m -R ¹³ - or phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine, atom chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,

Z is -O-, -CO-, -CO-O-,

-O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -,

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

• m is 0, 1, 2 3 4 5 or 6, R ¹³ is an atom H, trifluoromethyl, pentafluoro- ethyl group, heptafluoropropyl group, cycling alkyl group containing 3, 4, 5, 6, 7 or 8 atoms

carbon, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, thienyl, or a nitrogen heterocycle containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein the phenyl group, the thienyl group and the nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,

R ¹⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or

R ¹⁵ and R ^{1 S} are a chain of 4 or 5 methylene groups, of which one can be replaced by -0-, -S-, -NH-, -N _(CH3) - or --N (benzyl) -.

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

Y ¹ and Y ² together represent a sulfur atom, and Y ³ and Y ⁴ each represent -CR ¹² -, the radicals R ¹² are independent and have the meaning given to Y ¹ , Y

Y ³ , Y ⁴

R ³ is R ¹⁷ -CxH2xNR ¹⁸ - or R ¹⁷ -CxH ₂ -, wherein one methylene group of _X C _X H 2 can be replaced by -0-, -CO-, -S-, -S0-, group -SO 2 or -NR ¹⁹ -,

R ¹⁹ is a hydrogen atom, a methyl group or an ethyl group,

R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, trifluoromethyl, pentafluoroethyl or heptafluoropropyl, x is 0, 1, 2, 3, 4, 5, 6 , 7, 8, 9, or 10,

R ¹⁸ is a hydrogen atom or an alkyl group containing 1, 2, 3,

4, 5, 6, 7 or 8 carbon atoms, or

R and R together represent a bond unless x is less than a, ko 3, or

R ³ phenyl unsubstituted or with 2 substituents selected from fluorine, chlorine, atom is or substituted with 1 group consisting of bromine, iodine, trifluoromethyl amino, ethyl, nitro, cyano hydroxyl, methyl methoxy, dimethylamino group, group, group,

sulfamoyl sulfonylamino a methylsulfonyl group; group, methyl or R ³ and R ⁴ together represent alkylene chain containing 3, 4, 5, 6, 7 or 8 carbon atoms, while one methylene group

the alkylene chain may be replaced by -O-, -CO-, -S-, -SO-, or -SO2-,

R ⁴ is C _y H 2 _y R ²⁰ / wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CH = CH-, -C? C-, -CO-, -C0- 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 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 .

16, 17, 18, 19 or 20

0

R is hydrogen, methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -NR ²² R ²³ , phenyl, thienyl or a nitrogen heterocycle containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine , chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,

R ²² and R ²³ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or

R ( ²²⁾ and R ( ²³⁾ together are a chain of 4 or 5 methylene groups, one of which may be replaced by -O-,

-N (CH ₃ ) - or

-S-, by a group

-NH-, a group with a group

-N (benzyl)

Are you

R ⁵ is a hydrogen atom or together with R ¹¹ means a bond, in all its forms and mixtures thereof in any ratio, stereoisomeric as well as their physiologically acceptable salts.

Preferred are compounds of formula I wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ³ are as defined above, wherein none of the radicals R 2 ³ and R ⁴ , especially R ³ , is not a hydrogen atom; and furthermore, the compounds of formula I wherein none of R ³ and R ⁴ is a hydrogen atom, in all their stereoisomeric forms and mixtures thereof in any ratio, as well as their physiological usable salts.

Particularly preferred are compounds of formula I wherein:

X ¹ is -O-, -S-, -SO-, -SO ² -, -CR ¹ R ² -, or -NR ⁶ -,

R ¹ and R ² are independently hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, alkyl containing 1, 2, 3,

4 or 6 carbon atoms or a phenyl group unsubstituted or substituted by 1 or 2 substituents, from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group a group, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, or

R ¹ and R ^:

R ^s

R ⁹ n

R ⁸ together represent an alkylene chain containing 2, 3, 4, 5,

6, 7, 8, 9 or 10 carbon atoms, a hydrogen atom or a group -C n H 2n _n ^- R ^{8 is} <wherein one methylene group of the group _H2n can be replaced by -0-, -CH = CH-, -C = C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ -, -NR ⁹ -, or -CONR ^9- , is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, is 0, 1, 2, 3, 4, 5, 6, 7 or 8, is a hydrogen atom, an ethyl trifluoromethyl group, a pentafluoroheptafluoropropyl group containing 3, 4 , 5, group, carbon, dimethylamino, diethylamino ridyl, 1-pyrrolidinyl, 4-morpholialkyl, or 6, cycloatoms

1-pipenyl,

4-methylpiperazin-1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein the pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine atom, bromine atom, iodine atom, trifluoromethyl amino group, nitro group, cyano group, hydroxyl group, methyl methoxy group, dimethylamino sulfamoyl group, methylsulfonyl group and phonylamino ethyl group, group, group, group, group, methylsulje the group -CR ¹ R ² -, wherein the radicals R ¹ and R ² are defined at X ¹ but are independent of the radicals X ¹ ,

X ³ is -CR ¹ R ² -, wherein R ¹ and R ² are as defined in

X ¹ , but are independent of X ¹ residues,

X ⁴ is CR ¹ R ² -, -NR ⁶ -, -NR ¹¹ - or -CH (OR ³⁰ ) -, wherein the radicals R ¹ , R ² and R ⁶ are as defined in X ¹ but are on X ¹ residues independent,

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 represents a bond,

Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² - or a nitrogen atom, with a maximum of 2 groups of Y ¹ , Y ² , Y ³ and Y ^{4 being} simultaneously a nitrogen atom,

R ¹² is independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms cyano, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, azide, nitro, -ZC _m H _2m -R ¹³ - or phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine, atom chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,

Z is -O-, -CO-, -CO-O-,

-O-CO-, -S-, -SO-, -SO ₂ -, -SO ₂ NR ¹⁴ -, -NR ¹⁴ -, or -CONR ¹⁴ -,

R ¹⁴ is hydrogen or alkyl having 1, 2 or 3 carbon atoms is 0, 1,

2, 3, 4, 5 or 6

R ¹³ is an atom

-NR ¹⁵ R ¹⁶ , hydrogen, trifluoromethyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -CONR ¹⁵ R ¹⁶ , group, thienyl containing 1, 2, group

3

4, 5, 6, -OR ^30a , a phenyl or nitrogen heterocycle of 7, 8 or 9 carbon atoms, wherein the phenyl heterocycle is a group, thienyl and nitrogen unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl amino group, an ethyl group, a nitro group, a cyano hydroxyl group, a methyl methoxy group, a dimethylamino sulfamoyl group, a methylsulfonyl group and a group, a group, methylsulfonylamino group,

R ¹⁵

R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or

R ¹⁵ a

R ¹⁶ together represent a chain of 4 or 5 methylene may be replaced by -O-, -NH-, -N (CH3) - or one of which

-S-, by group, by group

-N (benzyl) -, _R 30a is hydrogen, atoms, carbon containing 1, or acyl containing or 3

1, 2, 3 or 4 carbon atoms; or

Y ¹ and Y ² together represent a sulfur atom and Y ³ and Y ⁴ are each -CR ¹² -, the radicals R ¹² are independent and defined at Y ¹ , Y ² , Y ³ , Y ⁴ ,

R ³ is a group R ¹⁷ -CxH ² x NR ¹⁸ - or a group R ¹⁷ -CxH ₂ -, wherein one methylene group of the group C _x H _{2 -} may be replaced

-O-, -CO-, -S-, -SO-, -SO ₂ - or -NR ¹⁹ -, R ¹⁹ is a hydrogen atom, a methyl group or an ethyl group, R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, trifluoromethyl, pentafluoroethyl or C3F7, x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R ¹⁸ is a hydrogen atom or an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

or

R ¹⁸ and R ¹⁷ together represent a bond unless x is less than 3, or

R ³ is a phenyl group unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl, nitro, cyano, amino, hydroxy, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino group,

or

I,

R ³ and R ⁴ together represent an alkylene chain containing 3, 4, 5, 6, 7 or 8 carbon atoms, one methylene group of the alkylene chain being replaced by -O-, -CO-, -S-, -S- SO- or -so ₂ -,

R ⁴ is C _r H 2 _N ^- R ^20, wherein one methylene group of the group C _r H2r can be replaced by -0-, -CH = CH-, -C = C-, -C0-, the group -C 0 -0-,

-O-CH-, -S-, -SO-, -SO ₂ -, -NR ²¹ -, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 R ²⁰ is hydrogen, methyl, trifluoromethyl, pentafluoroethyl, C3F7, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -NR ²² R ²³ , phenyl, thienyl or nitrogen containing 1, 2, 3 , 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, R ²² and R ²³ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms,

or

R ²² and R ²³ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N (benzyl) -, R ⁵ is hydrogen or together with R ¹¹ represents a bond, within all its stereoisomeric forms and mixtures thereof

in any ratio, as well as their physiologically acceptable salts.

Even more preferred are compounds of formula I wherein

X ¹

R ¹ and R ';

R ¹ and R '

R ⁵

R ⁹ n

R ⁸ is -O-, -S-, -SO ₂ -, -SO ₂ -, -CR ¹ R ² -, -NR ⁶ -, are independently hydrogen, trifluoromethyl, alkyl containing 1, Together, 2, 3, 4, 5 or 6 carbon atoms, taken together, represent an alkylene chain containing 2, 3, 4, 5 or 6 carbon atoms, is a hydrogen atom or a -C _n H 2 _n ^- R ^{8 group} , one methylene group of the C _n group H _2n may be replaced by -O-, -CH = CH-, -C ^C-, -CO-, -CO-O-, -O-CO-, -S-, - SO-, -SO ₂ -, -NR ⁹ -, or -CONR ⁹ -, is hydrogen or alkyl having 1, 2 or 3 carbon atoms, is 0, 1, is,

2, 3, 4, 5, 6, 7 or 8, hydrogen, trifluoromethyl, cycloalkyl carbon atoms containing 3, 4, 5 or 6 dimethylamino, diethylamino, 1-pyrrolidinyl, 4-methylpiperazine- 1-yl, pin, thienyl, imidazolyl

1-piperidinyl

A 4-morpholinyl pyridyl group or a phenyl group, an imidazolyl unsubstituted group wherein the pyridyl, thienyl and phenyl substituted with 1 or 2 or 2 substituents are fluorine, a chlorine atom selected from the group consisting of a bromine atom, a trifluoromethyl amino group, ethyl a group, a group, a hydroxyl methoxy group, a nitro group, a cyano group, a methyl dimethylamino iodo group, a group, a group, a group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group,

X ² is -CR 1 R ² -, wherein R ¹ and R ² are as defined in

X ¹ , but are independent of X ¹ residues,

X ³ is -CR ¹ R ² -, wherein R ¹ and R ² are as defined in

X ¹ , but are independent of X ¹ residues,

X ⁴ is CR ¹ R ² -, -NR ⁶ -, -NR ¹¹ - or -CH (OR ³⁰ ) -, wherein the radicals R ¹ , R ² and R ⁶ are as defined in X ¹ but are on X ¹ residues independent,

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 represents a bond,

Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² R ¹² is independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3, 4 or 5 carbon atoms , a cycloalkyl group containing 3,

4, 5 or 6 carbon atoms, a cyano group, a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a group ZC _{m r and} H 2 R ¹³ -, or phenyl,

N ₃ , nitro group, unsubstituted or substituted by a group of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl an ethyl group, a methoxy group, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group,

Z is -O-, -CO-, -CO-O-,

-0-C0-, -S-, -S0-, -SO2- or a group -SO 2 NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -,

R ¹⁴ is hydrogen or alkyl having 1, 2 or 3 carbon atoms is 0, 1,

2, 3, 4, 5 or 6

R ¹³ is an atom of the group -NR ¹⁵ R ¹⁶ , hydrogen, trifluoromethyl, cycloalkyl of 5 or 6 carbon atoms, -CONR ¹⁵ R ¹⁶ , with the group containing 3, 4, thienyl group

3

4, 5, 6, -OR ^30a , phenyl or nitrogen heterocycle of 7, 8 or 9 carbon atoms, unsubstituted or substituted 1-group containing 1, 2, thienyl and nitrogen, wherein the phenyl heterocycle is or 2 substituents selected from, consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl amino group, ethyl group, nitro group, cyano hydroxyl group, methyl methoxy group, dimethylamino sulfamoyl group, methylsulfonyl group, group, group, sulfonylamino group,

R ¹⁵

R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, methyl or

R ¹⁵ and R ¹⁶ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N '(benzyl) ) -,

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

Y ¹ and Y ² together represent a sulfur atom and each of Y ³ and Y ⁴ is -CR ¹² -, the radicals R ¹² are independent and defined at Y ¹ , Y ² , Y ³ , Y ⁴ ,

R ³ is R ¹⁷ -CxH2xNŔ ¹⁸ - or R ¹⁷ -CxH ₂ -, wherein one methylene group of the group C _x H _2x can be replaced by -0-, -C0- group, -S-, -SO-, -SO ₂ - or -NR ¹⁹ -,

R ¹⁹ is a hydrogen atom, a methyl group or an ethyl group,

R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, trifluoromethyl « a pentafluoroethyl group or a heptafluoropropyl group, r X is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R ¹⁸ is a hydrogen atom or an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

or

R ¹⁸ and R ¹⁷ together represent a bond unless x is less than 3, or

R ³ is a phenyl group unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group, R ⁴ It is C _y H _2y -R ^20, wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CH = CH-, -C? C- group, -C0- group, a group -C0-0- , -O-CO-, -S-, -SO-, -SO ₂ -, -NR ²¹ -, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms,

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

R is methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -NR ²² R ²³ , phenyl, thienyl or nitrogen containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl a nitro group, a cyano group, an amino group, a hydroxyl group, a methyl group, an ethyl group, a methoxy group, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group,

R ²² and R ²³ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or

R ²² and R ²³ together denote chain 4 or one of which may be replaced

-NH-, -N (CH 3) -S-, methylene, -O-, or

-N (benzyl) -,

R ⁵ is a hydrogen atom or together with R ¹¹ means a bond, in all its ratios, in any stereoisomeric form, and in their physiologically acceptable salt mixtures.

Particularly preferred are compounds of formula I in which:

X ¹ is -O- or -CR ¹ R ² -,

R ¹ and R ² are independently hydrogen, trifluoromethyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

X ²

X ³

X ⁴

R ³⁰

Y ¹ , y ² , the radicals being the group -CR ¹ R ² -> wherein the radicals R ¹ and R ² are defined at X ¹ but are independent of the radicals X ¹ , the group -CR ¹ R ² - is wherein the radicals R ¹ and R ² are as defined at X ¹ , but are independent of X ¹ , CR ^{1 is} R ² - or -CH (OR ³⁰ ) -, wherein R ¹ and R ² are as defined at X ¹ , but are at the radicals X ¹ independently is H, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms,

Y ³ and Y ⁴ are independently -CR ¹² R ¹² are independently hydrogen, fluoro, chloro, bromo, iodo, 1, 2,

3, 4 or 5 carbon atoms, a cyano group, a trifluoro methyl group, a nitro group, a group ZC _m H ₂ m ^{_ 13_} R or a phenyl group unsubstituted or substituted, or 2 substituents, which are F, Cl, bromo, iodo, trifluoromethyl amino, ethyl, nitro, cyano hydroxyl, methyl methoxy, dimethylamino, group, group, sulfamoyl, methylsulfonyl and methylsulfonylamino,

FROM

R ¹⁴ m

R ¹³ is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, it is hydrogen or alkyl having 1, 2, or 3 carbon atoms is 0, 1, 2 or 3, is hydrogen, trifluoromethyl, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, thienyl 21

or a nitrogen-containing heterocycle containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the phenyl, thienyl or nitrogen-containing heterocycle being unsubstituted or substituted by 1 or 2 substituents from the group consisting of a fluorine atom , chlorine, bromine, iodine, trifluoromethyl, nitro, ¹ cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, R ¹⁵ a R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms,

or

R ¹⁵ a R ¹⁶ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N (benzyl) -. R ^30a is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms, R ³ R ¹⁷ is a radical -C _x H _2x ~. R ¹⁷ is a methyl group, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms or trifluoromethyl, x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R ⁴ It is C _y H _2y -R ^20, wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CO-O-, -O-CO-, -NR ²¹ - or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms,

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

A Λ

R is methyl, trifluoromethyl or cycloalkyl having 3, 4, 5 or 6 carbon atoms,

R ⁵ is hydrogen, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts.

Almost most preferred are compounds of formula I wherein:

X ¹ is -O- or -CH ₂ -,

X ² is -CR ¹ R ² -,

R ¹ and R ² are independently hydrogen or alkyl having 1, 2, or 3 carbon atoms,

X ³ is methylene or -C (CH ₃ ) ₂ -,

X ⁴ is a methylene group or a -CHOH- group,

Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ^12, R ¹² are independently hydrogen, fluoro, chloro, bromo, alkyl having 1, 2 or 3 carbon atoms, cyano, trifluoromethyl , nitro, -ZC _m H _2m -R ^13- , i

Z is -O-, -CO-, -CO-Ο-,

-O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -,

R ( ¹⁴⁾ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, m is 0, 1, 2 or 3,

R ¹³ is hydrogen, trifluoromethyl, -NR ¹⁵ R ¹⁶ , phenyl, piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl or imidazolyl,

R ⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms,

R ³ is a group R ¹⁷ -C _x H _2x ,

R ¹⁷ is a methyl group, x is 0, 1, 2 or 3,

R ⁴ is C _r H _2r -R ²⁰ , wherein one methylene group of C _r H _2r may be replaced by -O-, -CO-O-, -O-CO-, -NR ²¹ -, or -CONR ²¹ -,

R ²¹ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5 or 6,

R ²⁰ is methyl; trifluoromethyl or pyridyl,

R ⁵ is hydrogen, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts.

Most preferred are compounds of formula I wherein:

X ¹ is -O-,

X ² is -CR ¹ R ² -,

R ¹ and R ² are independently hydrogen, alkyl containing 1,

2 or 3 carbon atoms,

X ³ is methylene or -C (CH ₃ ) ₂ -,

X ⁴ is a methylene group,

Y ¹ is CH, Y ² is CH, Y ⁴ is CH, Y ³ is -CR ¹² -, R ¹² is a fluorine atom, a chlorine atom, a bromine atom, an alkyl group containing 1, 2 or 3 carbon atoms, a cyano group, trifluoromethyl, nitro, -ZC _m H _2m -R ¹³ -, FROM is -O-, -CO-, -CO-Ο-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ² NR ¹⁴ - or -CONR ¹⁴ - R ¹⁴ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms,

m is 1, 2 or 3, R ¹³ is hydrogen, trifluoromethyl, pyridyl or phenyl, R ³ is R ¹⁷ -C _x H _2x -, R ¹⁷ is methyl, x is 0, 1 or 2 R ⁴ ' is a group C _r H _2r -R ²⁰ z, wherein one methylene group of the group C _r H _2r may be replaced by -O-, -CO-O-, -O-CO-, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5 or 6, R ²⁰ is methyl or trifluoromethyl, R ⁵ is hydrogen,

, 25 in all their stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts.

Alkyl and alkylene are also branched. it

C _m H ₂ mr CXH _2x and radicals may be linear or alkylene radicals of the formula C _n H _2n, C _r H _2r. Alkyl linear or branched aa. the alkylene radicals may be substituted or, if present, in other alkylmercapto radicals, or in e.g.

Examples are a group, an alkyl n-propyl group, in an alkoxy moiety of a fluorinated alkyl or moiety.

the residues are methyl, isopropyl isobutyl tert-butyl, group, n-butyl sec-butyl, isopentyl ethyl, n-pentyl neopentyl, n-hexyl, 3,3-dimethyl, heptyl, octyl, nonyl decyl, undecyl, group, tetradecyl, butyl, group, tridecyl dodecyl, hexadecyl, heptadecyl nonadecyl, eicosyl pentadecyl, octadecyl, octadecyl.

Examples of alkylene radicals are divalent radicals derived therefrom, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene,

2,2-propylene group,

1,3-propylene, 1,4-butylene,

1,5-pentylene group,

2,2-dimethyl-1,3-propylene, 1,6-hexylene, and the like. Examples of acyl residues ^! are formyl, acetyl, propionyl, n-butyryl or isobutyryl.

Nitrogen heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are mainly 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-, and -3- or - 5-yl, 1- or 5-tetrazolyl, -2-, 4- or

Z6

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-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl group,

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-cinnolinyl, 2-, 3-, 5-, 6-, 7- or

8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.

Particularly preferred are the following nitrogen-containing heterocyclic groups: pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Thienyl means 2- and 3-thienyl.

Monosubstituted phenyl radicals may be substituted at the 2-, 3- or 4- positions, disubstituted at the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5- positions . Analogously, this also applies to nitrogen heterocycles or thiophene residues.

In the case of disubstitution, the residues may be the same or different.

When the radicals R ^{@ 1} and R @ ² together represent an alkylene chain, they form, with the nitrogen atom carrying them, a ring which has one carbon atom in common with the seven-membered ring in formula I and is a spiro compound. When R ⁷ and R ¹⁰ together represent a bond, this means that there is a double bond between the groups X ¹ and X ² . That is, when R ⁵ and R ¹¹ together are a bond, the group X is ⁴ and the carbon atom carrying the radical R ³ -SO 2 NR ⁴ double bond. When R ¹⁷ and R ¹⁸ together are a bond, the group R ¹⁷ -CxH2x-NR ¹⁸ -, preferably a nitrogen heterocycle bonded via a nitrogen atom. When R ¹⁷ and R ¹⁸ together represent a bond and R ¹⁷ -CxH ₂ -NR * ⁸ - is a nitrogen-containing heterocycle attached through a nitrogen atom, the nitrogen-containing heterocycle is preferably a 4-membered or larger ring e.g. 5-membered ring, 6-membered ring, or 7-membered ring. When Y ¹ and Y ² together represent a sulfur atom, the structural element -γ ² = γ ^Α - is the group -S-, so that the 7-membered ring in formula I is fused to the thiophene ring in this case.

When the compounds of formula I contain one or more acidic or basic groups e.g. one or more basic heterocycles are within the scope of the present invention; and physiologically or toxicologically acceptable salts, especially pharmaceutically acceptable salts. Likewise, the compounds of formula I may have acidic groups e.g. one or more carboxyl groups and may be used e.g. as alkali metal salts, especially sodium or potassium salts, or alkaline earth metal salts e.g. calcium or magnesium, or as ammonium salts e.g. salts of ammonia or organic amines or amino acids. Compounds of formula I having one or more basic i.e. protonatable groups, or containing one or more basic heterocyclic rings, may also be in the form of their physiologically usable acid addition salts of inorganic or organic acids, e.g. such as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malate, gluconates and the like. If the compounds of the formula I contain simultaneously acidic and basic groups in the molecule, the invention includes, in addition to the salts mentioned, the internal salts of the so-called. betaines. Salts of the compounds of formula I can be obtained by conventional procedures, e.g. by coupling with an acid resp. with a base in a solvent or dispersant, or alternatively by ion exchange with another salt.

The compounds of the formula I can be present in stereoisomeric forms by said substitution. If compounds of formula IEntalten compounds of formula I contain one or more asymmetric centers, they may have independently

S or R. All possible stereoisomers, e.g.

enantiomers or diastereoisomers, and mixtures of two or more stereoisomers e.g.

enantiomers and / or diastereoisomers, in any ratios. The enantiomers may be e.g. pure enantiomeric forms both dextrorotatory and left-handed antipodes and also mixtures of both enantiomers in different proportions or in the form of racemates. When cis / trans isomerism occurs, both cis and trans forms and mixtures thereof are included. The individual stereoisomers may, if desired, be obtained by separating the mixture according to conventional procedures or e.g. by stereoselective synthesis.

In the presence of movable hydrogen atoms, the invention also relates to all tautomeric forms of the compounds of formula I.

The compounds of formula I may be prepared by a variety of chemical processes, e.g. so that

a) reacting a compound of formula IIa or IIb

wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ⁵ are as defined above and L. is a nucleofugic leaving group, especially a conventional nucleofugic group such as e.g. a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, in known manner from the sulfonamide or its salts of formula III

(III)

29th

wherein R ³ and R ⁴ are as defined above and M is a hydrogen atom or more preferably a metal atom, especially lithium, sodium or potassium, or in the case of reaction with a compound of formula IIb a trialkylsilyl group e.g. trimethylsilyl group or that is

b) reacting the compound of formula IV

(IV) wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ⁵ are as defined above, with a sulfonic acid derivative of the formula V

(V) wherein R ³ is as defined above and W is a nucleophagic leaving group such as e.g. a fluorine atom, a bromine atom, a 1-imidazolyl group, but especially chlorine or

compound of formula

(VI) wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ ; Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ⁵ are as defined above, are subjected to an alkylation reaction with an alkylating agent of formula VII in a known manner

R ⁴ -L (VII) wherein Ŕ ⁴ is as defined above except hydrogen and 'L is as defined above, or

d) conducting an electrophilic substitution reaction in a compound of formula I

R3

wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ⁵ are as defined above, in at least one position of Y ¹ to Y ⁴ , if the CH- group is in this position, or at least one of X ¹ and X ^{4 is} carried out by a chemical reaction, e.g. alkylation or acylation.

Process a) corresponds to the nucleophilic substitution of a leaving group in a reactive bicycle of the formula IIa or IIb with a sulfonamide and a sulfonamide, respectively. its salts of formula III.

For higher nucleophilicity and higher reactivity of the salt of said sulfonamide, its use is preferable to the use of free sulfonamide (formula

III, M

H) from which these (Formula III, M = metal cation) are prepared by treatment with a base. Using the free sulfonamide (Formula III, M = H), its deprotonation to the salt can be carried out in situ. Preference is given to bases which do not self-alkylate or alkylate very little, such as e.g. sodium carbonate, potassium carbonate, sterically protected amines e.g. dicyclohexylamine, N, N-dicyclohexyl 31 ethylamine or other strong nitrogen bases with low nucleophilicity e.g. DBU (diazabicycloundecene)

N, N ', N' '' - -triisopropylguanidine

Of course, other conventional bases such as potassium tert-butoxide, sodium ethoxide, alkaline bicarbonates, alkali hydroxides such as e.g. LiOH, NaOH or KOH, or alkaline earth hydroxides such as e.g. Ca (OH) ₂ .

In the case of the reaction of an epoxide of formula IIb with a trialkyl or trimethyl silylsulfonamide of formula III, it is preferable to work in the presence of a fluoride e.g. tetrabutylammonium.

Preferably, the reaction is carried out in a solvent, in particular a polar organic solvent such as e.g. dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetramethylurea (TMU), hexamethylphosphoric triamide (HMPT), tetrahydrofuran (THF), dimethoxyethane (DME) or another ester or e.g. also in a hydrocarbon such as toluene or a halogenated hydrocarbon such as chloroform or methylene chloride and the like. It is also possible to work in a polar protic solvent such as e.g. water, methanol, ethanol, isopropanol, ethylene glycol, or oligomers and semi-ethers thereof. The reaction may also be carried out in a mixture of these solvents. Likewise, the reaction can be carried out completely without solvent. The reaction is preferably carried out at a temperature of -10 to +140 ° C, particularly preferably at a temperature of 20 to 100 ° C. Phase transfer catalysis may also be advantageously used.

Compounds of formula IIIa can be obtained by methods described in the literature e.g. from the corresponding alcohols of formula IIIa (L = ^{cf 1} I)

OH, R = H) by treatment with a halide of the formula HL (L = Cl, Br, I) or an inorganic acid chloride e.g. POCl3, ΡΠ3, PCl5, SOCl2, sobre ₂₎ and e.g. by radical halogenation of said compound of formula IIIa (L = H and R ⁵ = H) with elemental chlorine or bromine or a radically activated halogenating agent such as e.g. N-bromosuccinimide (NBS) or sulfuryl chloride (SO ₂ Cl ₂ ). In the case of radical halogenation, it is generally carried out in the presence of an initiator such as an energy rich UV or visible light or a chemical initiator e.g. azodiisobutyronitrile.

Compounds of formula IIa in which X ⁴ is -NR ¹¹ - and R ⁵ together with R ¹¹ represents a bond can be obtained e.g. from the corresponding lactam of formula IIa (L and R ⁵ together are carbonyl oxygen, X ⁴ = NH) by treatment with an inorganic acid halide e.g. POC1 ₃ , PC15 ₅ , SOC1 ₂ SOBr ₂ ).

Compounds of formula IIb can be obtained by methods known in the literature from the corresponding olefins of formula IIc

(IIc) wherein X ¹ , X ² , X ³ , Y ¹ , Y ² , Y ³ and Y ⁴ are as defined above, e.g. by treatment with suitable inorganic or organic peroxides, e.g. H2O2 or m-chloroperbenzoic acid, or base-catalyzed cyclization corresponding to bromohydrin, obtained from the cheeks e.g. by reaction with N-bromosuccinimide and water.

The epoxides of formula IIb can also be obtained from the olefins of formula IIc in optically pure form by oxidation in the presence of chiral Jacobsen catalysts (see Tetrahedron Lett. 32, 1991, 5055).

Process (b) corresponds to a known and frequently used reaction of a reactive sulfonyl compound of formula V, in particular a chlorosulfonyl compound (W = Cl), with an amino derivative of formula IV to give the corresponding sulfonamide derivative of formula I. The reaction is carried out in a solvent, preferably polar and particularly preferably in the presence of a base, which can itself be used as a solvent (e.g. triethylamine or especially pyridine and its homolog). Suitable solvents are e.g. water, aliphatic alcohols e.g. methanol, ethanol, isopropanol, sec-butanol, ethylene glycol, monoalkyl and dialkyl ethers of monomeric and oligomeric ethylene glycols, tetrahydrofuran, dioxane, dialkylated amides such as dimethylformamide (DMF), dimethylacetamide (DMA), tetramethylurea (TMMP) and hexamethylfluoramide. The process is carried out at a temperature of 0 to 160 ° C, preferably 20 to 100 ° C.

The amines of formula IV are obtained by a method according to the literature, preferably from the corresponding carbonyl compound of formula VIII

wherein X ¹ , X ² , X ³ , X ", Y ¹ , Y ² , Y ³ and Y ⁴ are as defined above and A is an oxygen atom, and ammonia or an amine of formula IX

R ⁴ - NH ₂ (IX) wherein R ⁴ is as defined by reduction or catalytic reduction, preferably at a higher temperature and in an autoclave. First, the in situ condensation reaction of a ketone of formula VIII (A = oxygen) and an amine of formula IX is formed by a Shiff base of formula VIII in which A is a group R ⁴ -N =. Said base can be converted directly to the amine of formula IV by reduction, i.e. without isolation. This can also be accomplished by condensation of an intermediate compound of formula VIII and IX to isolate the resulting Schiff base '(formula VIII, A is an R ⁴ -N = group) according to the literature. In a subsequent separate step with a suitable reducing agent such as e.g. NaBH ₄ , LiAlH ₄ , NaBH ₃ CN or catalytic hydrogenation in the presence of e.g. Raney nickel or precious metal e.g. palladium to give the compound of formula IV.

Compounds of formula IV in which R ⁴ is hydrogen may be advantageously obtained by literature procedures, also by reduction of oximes or oxime ethers / formula VIII, A is = N-OR, R = H or alkyl) or hydrazones ( formula VIII, A is = N-NR ² , R is e.g. H or alkyl) e.g. using complex metal hydrides or catalytic hydrogenation. The required oximes and hydrazones are preferably prepared in a known manner from ketones of formula VIII (A is oxygen) and hydrazine or a derivative thereof or e.g. hydroxylamine hydrochloride while removing the water formed.

Process (c) represents a known alkylation reaction of a sulfonamide, respectively. a salt thereof (Formula VI) with an alkylating agent (Formula VII) and is analogous to and conducted under the same conditions as in Reaction a).

The preparation of the sulfonamide derivative of formula VI and its intermediate is described in detail in step. The preparation of the alkylating agent of formula VII is analogous to literature procedures e.g. preferably from the corresponding hydroxy derivative (Formula VII, L = hydroxyl group).

Process d) corresponds to a further chemical conversion of compounds of formula I in accordance with the present invention into other compounds of formula I in accordance with the present invention e.g. electrophilic substitution at one or more of the positions designated Y ¹ and Y ⁴ when these are CH. Preferred substitution reactions are

1. aromatic nitration to introduce one or more nitro groups which can be reduced (by some or all) to amino groups by a subsequent reaction. Amino groups can be converted to other groups, e.g. Sandmeyer reaction e.g. for the introduction of cyano groups,

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

3. chlorosulfonation e.g. by the action of chlorosulfonic acid to introduce a chlorosulfonyl group, which can be converted to other groups, e.g. to a sulfonamide group,

4. Friedel-Cafts acylation for introducing acyl or sulfonyl residues by treatment with the corresponding acid chloride in the presence of Lewis acid as Friedel-Crafts catalyst, preferably in the presence of anhydrous aluminum chloride.

As further chemical transformations of the compounds of formula I in accordance with the present invention, e.g. the reaction at positions X ¹ to X ⁴ . Thus, e.g. of a compound of formula I in accordance with the present invention (X ⁴ = CHOH) by alkylation or acylation of a compound of formula LR ³⁰ , wherein L is as defined above and R ³⁰ is as defined above except hydrogen to the corresponding alkyl or acyl derivative of formula I (X ⁴ is CHOR ³⁰ ). Further, it can be eliminated by treatment with a dehydrating agent of the hydroxyl group to give compounds of formula I wherein R ⁵ and R ¹¹ together represent a bond.

In all processes, it may be advantageous for some reaction steps to temporarily protect some functional groups in the molecule. Such protection techniques are well known to those skilled in the art. The selection of a protecting group for a given group and the procedure for its introduction and removal are described in the literature and can be readily adapted in individual cases without difficulty.

The bicyclic intermediates for the above processes are either known from the literature or can be prepared analogously. Some methods for preparing these intermediates are described e.g. in the following articles: 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 stated that the compounds of formula I surprisingly strongly and specifically block (close) the K ⁺ channel which has been opened by cyclic adenosine monophosphate (cAMP) and is different from the basic well known K ⁺ (ATP) channel, and that this in the coarse tissue the intestine found in the K ⁺ (cAMP) channel is very similar, perhaps even identical, to the I _KS 'channel of cardiac muscle. For the compounds according to the invention it is possible to show a strong blocking action on the _IKs channel ^_ guinea-pig cardiomyocytes and on Xenopus oocytes. As a result of this blocking method

K ⁺ (cAMP) -channel resp. The _Ks -channels can induce compounds in accordance with the present invention with highly therapeutically useful pharmacological effects in living organisms and exert an excellent drug action for the treatment and prophylaxis of various diseases.

Thus, the compounds of formula I in accordance with the present invention appear to be a new effective class of inhibitors of stimulated gastric acid secretion. The compounds of formula I are therefore valuable drugs for the treatment and prophylaxis of gastric and digestive ulcers e.g. duodenum. They also appear to be excellent drugs for the treatment and prophylaxis of reflux esophagitis due to their strong action against gastric juice secretion.

The compounds of formula I in accordance with the present invention are further characterized by anti-diarrhea action and are therefore useful as medicaments for the treatment and prophylaxis of diarrhea.

The compounds of formula I in accordance with the present invention are furthermore useful as medicaments for the treatment and prophylaxis of circulatory diseases. In particular, they can be used for the treatment and prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, and in particular, cardiac arrhythmias which can be eliminated by prolonging the action potential. In particular, they can be used for the treatment and prophylaxis of atrial fibrillation (atrial oscillation), and thus for the treatment and prophylaxis of reentry arrhythmias, and for preventing sudden cardiac death due to ventricular oscillation.

Although a large number of antiarrhythmic agents are already on the market, there are no compounds available that are truly satisfactory in terms of efficacy, widespread use and side-effect profile, so that there remains a need to develop improved antiarrhythmics. The action of numerous known antiarrhythmic agents, the so-called. Class III is based on increasing myocardial refractive time by increasing the duration of action potential. This is essentially due to the degree of repolarized K ⁺ -flow that flows from the cell through different K ⁺ -channels. Especially great importance is attributed to the so-called. “Delayed rectifier I _K , from which there are two subtypes, one accelerating I _Kr and one slowing I _Ks · Most known class III antiarrhythmic drugs block predominantly or only I _Kr (eg Dofetilide, d-Sotalol). However, these compounds have been shown to exhibit an increased antiarrhythmic risk at low or normal heart rate, with mainly arrhythmias being observed, referred to as "Torsades de pointes" (DM Roden, "Current Status of Class III Antiarrhythmic Drug Therapy Am. J. Cardiol"). 72 (1993), 44B -49B On the other hand, with increased heart rate and R-receptor stimulation, the effect on prolonging the action potential of the I _Kr- blocking agent is substantially reduced, suggesting that under these conditions I _Kr contributes to repolarization stronger. For these reasons, the substances according to the invention foreseen, that block the _IKs, a substantial advantage over known compounds that block I _Kr. Meanwhile, also described that a correlation exists between the inhibitory action on the _IKs channel identified as the life-threatening cardiac arrhythmias such as β-adrenergic hyperstimulation (BTJ Colatsky, CH Follme r and CF Starmer, "Channel Specificity in Antiarryhymic Drug Action, Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhytmias, Circulation 82 (1990), 2235 2242, AEBusch, K. Malloy, WJ groh, MD Varnum, JP Adelman and J. Maylie, "The novel class III antiarrhythmic drugs NE-10064 and NE-10133 inhibit I _Ks channels in xenopus oocytes and I _Ks in guinea pig cardiac myocytes, Biochem. Biophys. Res. Commun. 202 (1994) 265-270).

heart

Consequently, compounds of insufficiency, in particular, cause a marked improvement in cardiac insufficiency by congestive failure by both beneficial action and inhibitor action (positive inotropen), e.g.

Congestive Heart for the desired contraction of phosfordiesterase.

Despite the therapeutically beneficial benefits that can be achieved by blocking I _Ks , very few compounds have been described to inhibit this delayed rectifiers subtype. The substance Azimilide, which is being developed, also shows a blocking effect on

I _Ks , but mainly blocks I _Kr (selectivity 1: 10). WO-A-95/14470 claims the use of benzodiazepines as selective blockers of the _IKs - Other agents that block the _IKs are described in FEBS Letters 396 (1996), 271 - 275. "Specific blocade of slowly activating I _Ks channels by chromanols. ., Arch. - Eur. J. Fysiol. 429 (1995), 517-530. “A new class of CAMP-mediated Cl-secretion inhibitors in rabbit colon, acting by the reduction of cAMP-activated K ⁺ conductance. However, the ability of the compounds disclosed herein is less than that of the compounds of Formula I in accordance with the present invention.

The compounds of formula I in accordance with the present invention and their physiologically acceptable salts can be used as medicaments, alone, in a mixture or in the form of pharmaceutical compositions, in animals, preferably mammals, especially humans. The present invention also provides compounds of formula I and their physiologically acceptable salts for use as a medicament for the treatment and prophylaxis of known diseases and for the preparation of K ⁺ channel blocking drugs. The present invention further provides pharmaceutical compositions comprising, as an active ingredient, an effective dose of at least one compound of formula I and / or at least one physiologically acceptable salt thereof in addition to conventional, pharmaceutically acceptable carriers and additives. The pharmaceutical compositions normally contain 0.1 to 90 wt. the compounds of formula I and / or their physiologically acceptable salts. The preparation of the pharmaceutical compositions can be carried out by known methods, wherein the compounds of formula I and / or their physiologically acceptable salts are combined with one or more solid or liquid pharmaceutical carrier and / or excipient and optionally other medicaments in a form suitable for administration, which can then to be used as a medicine in human or veterinary medicine.

Medicaments containing the compounds of formula I in accordance with the present invention and / or their physiologically acceptable salts can be administered orally, parenterally, e.g. intravenously, rectally, by inhalation, or topically, the preferred administration varies, e.g. according to the symptoms of the disease being treated.

It is known to those skilled in the art which ingredients are suitable for the desired composition. In addition to solvents, suppository fillers, tabletting agents and other carriers, e.g. also antioxidants, dispersing agents, emulsifiers, foams, flavors, preservatives, surfactants, buffers and coloring agents.

The compounds of formula I can also be combined with other drugs to achieve the desired therapeutic effect. E.g. in the treatment of cardiovascular diseases, combinations with agents active in the cardiac circulation are preferred. As such, they are advantageous in cardiovascular diseases e.g. other class I, class II or class III antiarrhythmic drugs; I _K -channel blocking agents e.g. Dofetilide, or further, agents affecting blood pressure such as

ACE-inhibitors (eg Enalapril, Captopril, Ramipril), angiotensin antagonists, K ⁺ channel activators as well as α- and β-receptor blocking agents, but also sympathomimetic and adrenergic compounds as well as Na ⁺ / H ⁺ exchange inhibitors, Ca-channel antagonists, phosphodiesterase antagonists; digitalisglycoside or diuretics.

Further, the following combinations with antibiotics and anti-ulcer drugs, e.g. with H ₂ -antagonists (e.g.

ranitidine,

Cimetidine, Famotidine, etc.), especially when used to treat diseases of the digestive tract.

In preparing the oral form, the active compounds are mixed with suitable excipients such as carriers, stabilizers or inert diluents and converted into the desired form such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions by conventional means. As an inert carrier, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch, can be used. The composition can be prepared as dry or wet granules. As the oily carrier or solvent, e.g. vegetable or animal oil such as sunflower oil or fish oil. As a solvent for aqueous or alcoholic solutions, e.g. water, ethanol or sugar solution or mixtures thereof. Other additives for other applications are e.g. polyethylene glycol and polypropylene glycol.

For subcutaneous or intravenous administration of the active compound, they are mixed with conventional substances for this purpose, such as e.g. solvents, emulsifiers or others, in solution, suspension or emulsion. The compounds of formula I and their physiologically acceptable salts can also be lyophilized and the product obtained can be used e.g. for the preparation of injections or infusions. As solvents, for example, water, physiological saline solution or alcohol, e.g. ethanol, propanol, glycerin, in addition to a sugar solution such as glucose or mannitol, or else mixtures of the various solvents mentioned.

Suitable pharmaceutical forms for aerosol or spray administration are solutions, suspensions or emulsions of the active compound of the formula I or a physiologically acceptable salt thereof in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of these solvents. If desired, the composition may also contain other pharmaceutical additives such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a composition usually contains the active ingredient in a concentration of 0.1 to 10, in particular 0.3 to 3% by weight.

The dosage of the active compounds of the formula I or of the active compound to be administered is e.g. their physiologically tolerable salts vary from case to case and are adapted to the optimum effect in the circumstances. Naturally, they depend on the frequency of administration and the efficacy of the compound employed and the duration of administration for treatment or prophylaxis, but also on the mode and severity of the disease being treated as well as the sex, age, weight and condition of the patients treated and whether acute or prophylactic treatment. Typically, the daily dose of a compound of Formula I when administered to a patient weighing 75 kg is 0.001 mg / kg body weight to 100 mg / kg body weight, preferably 0.01 mg / kg body weight to 20 mg / kg body weight. The dose may be applied once or in multiple portions, e.g. two, three or four doses. Especially in the treatment of acute cases of cardiac rhythm disorders, e.g. in an intensive care unit, only parenteral administration by injection or infusion, e.g. intravenous long-term infusion. '

DETAILED DESCRIPTION OF THE INVENTION

List of abbreviations

DMA N, N-dimethylacetamide

DMSO dimethylsulfoxide

EA ethyl acetate

_Tc melting point (unless stated otherwise, refers to the crude product, without purification, m.p. pure product is thus obviously greater)

NBS N-bromosuccinimide

RT room temperature

TF tetrahydrofuran

Example 1

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

CH.

a) 5 g (28 mmol) of 8-fluoro-1-benzosuberone and 2.1 g (31 mmol) of hydroxylamine hydrochloride were heated to boiling in 20 ml of ethanol and 20 ml of pyridine for 5 hours. After the solvent was distilled off on a rotary evaporator, the remainder of the mixture with water was adjusted to pH 2 with dilute hydrochloric acid and stirred until the oily material crystallized. 5.1 g of 8 are obtained

-fluoro-1-benzosuberonoxime (m.p. 97-103 ° C), which is reduced to 3-fluoro-5-amino-6,7 by hydrogenation in methanol at normal pressure and at room temperature on Raney-nickel catalyst. , 8,9-tetrahydro-5H-benzocycloheptene.

Yield: 4.3 g, melting point hydrochloride 212-216 ° C.

b) To a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptane and 1.5 g (60 mmol) of triethylamine in 40 ml of tetrahydrofuran while cooling ice drips

2.3 g (18 mmol) of ethanesulfonic acid chloride. The mixture was allowed to warm to room temperature, stirred overnight, and then the solvent was distilled off in vacuo. After stirring the residue with water, the precipitated product is filtered off. 2.9 g of 3-fluoro-5- (N-ethylsulfonylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene are obtained, m.p. 118-121 ° C.

Example 2

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

To a suspension of 0.12 g (4.1 mmol) of 80% sodium hydride in 5 ml

A solution of 0.81 g (3 mmol) of 3-fluoro-5- (N-ethylsulfonyl-N-methylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene (Example 1) was added dropwise under N, N-N-dimethylacetamide. ) in 10 ml of N, N-dimethyl-

acetamide. After stirring at room temperature for 3 hours dropped 0.63 g (4.5 mmol) of methyl iodide at room temperature rooms is stirred overnight. The solvent was distilled off

the residue was mixed with water and extracted with ethyl acetate. After drying over magnesium sulfate, the organic phase is concentrated in vacuo. It will be obtained

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

Example 3

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

3-Fluoro-5- (N-ethylsulfonyl-N-butylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene was obtained analogously to Example 2, but from 0.12 g (4.1 mmol). % sodium hydride, 0.81 g (3 mmol)

3-fluoro-5- (N-ethylsulfonylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene and 0.82 g (4.5 mmol) of butyl iodide.

Yield: 0.88 g.

Example 4

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

(a) 2,3-Dihydro-7-nitro-benzoxepine

To a suspension of 50 g of 3,4-dihydro-7-nitro-1-benzoxepin-5 (2H) -one (J. Chem. Soc., Perkin Trans.l, 1991, 2763) in 345 ml of methanol at 0 ° C 10.2 g of sodium borate are added in portions with vigorous stirring. After 30 minutes, the reaction mixture was poured into ice water, the solid was filtered off to give 43 g of 7-nitro-2,3,4,5-tetrahydro-1-benzoxepin-5-ol, which was then heated with 1 hour for 1 hour. g of p-toluenesulfonic acid in 520 ml of toluene using an azeotropic extender. After cooling, the organic phase is washed with sodium carbonate solution and common salt. After drying over magnesium sulphate and evaporation, 38.8 g of 2,3-dihydro-7-nitro-1-benzoxepine are obtained. Melting point 98-100 ° C.

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

To a solution of 38.8 g of 2,3-dihydro-7-nitro-1-benzoxepine in 780 ml of dimethyl sulfoxide and 78 ml of water is added together with ice-cooling.

72.3 g of N-bromosuccinimide, raising the temperature to 30 ° C. After stirring at room temperature for 90 minutes, the reaction mixture was poured into 5 liters of ice water, stirred for 1 hour, and then the crystalline precipitate was filtered off with suction to give 60 g of bromohydrin. A solution of this bromohydrin in 465 mL of methanol was added dropwise at room temperature to a solution of 5.1 g of sodium in 400 mL of methanol. After stirring for 1 hour, the precipitated precipitate is filtered off with suction 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 123-125 ° C.

c) N-methyl-N-trimethylsilylethanesulfonamide

A mixture of 33 g of N-methylethanesulfonamide 101 g of hexamethyldisilazane and a pinch (at the tip of a spatula). ammonium chloride was heated at 100 ° C for 2 hours under argon, and then at 130 ° C for an additional hour. Distillation of the reaction mixture in vacuo afforded 42 g of N-methyl-N-trimethylsilylethanesulfonamide (b.p. 118-121 ° C / 10 Torr).

d) Trans-7-nitro-5- (N-ethylsulfonyl-N-methylamino) -2,3,4,5-tetrahydro-1-benzoxepin-4-ol; η ί '3'. '45'; '

To a mixture of 6 g of 4,5-epoxy-7 ^; hitro-2 _from 3,4,5-tetrahydro-1-benzoxepine and 9.5 g of N-methyl-N-trimethylsilylethanesulfonamide were added with stirring 2 g of tetrabutylammonium fluoride. The mixture was then heated at 65 ° C for 3 hours, stirred at room temperature overnight, and then poured into ammonium chloride solution. After extracting several times with ethyl acetate, the extract is washed with water and dried over magnesium sulfate. Evaporation and recrystallization of the residue from isopropanol gave 7.1 g of trans-7-nitro-5- (N-ethylsulfonyl-N-methylamino) -2,3,4,5-tetrahydro-1-benzoxepin-4-ol. Mp 133-135 ° C.

Example 5

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

To a mixture of 4 g of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepine-7-carbonitrile (J. Chem. Soc., Perkin Trans.l, 1991, 2763) and 7.0 g.

N-methyl-N-trimethylsilylethanesulfonamide was added with stirring

1.5 g of tetrabutylammonium fluoride. The mixture was then heated at 60 ° C for 3 hours, then stirred at room temperature overnight

I was poured into ammonium chloride solution. After extracting several times with ethyl acetate, the extract is washed with water and dried over magnesium sulfate. Evaporation and recrystallization of the residue from cyclohexane / ethyl acetate (1: 5) gave 3.2 g of trans-7-cyano-5- (N-ethylsulfonyl-N-methylamino) -2,3,4,5-tetrahydro-1-ol. benzoxepin-4-ol. M.p. 142-144 ° C.

Example 6

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

(ia) A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5 (2H) -one (J. Chem. Soc., Perkin Trans. 1, 1991 2763) and 4.63 g (68 mmol). hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine is heated at reflux for 5 hours. After the solvent was distilled off on a rotary evaporator, the residue was mixed with water and the mixture was adjusted to pH 2 with dilute hydrochloric acid and stirred for 3 hours. Filtration and drying of the precipitated product yielded 10.2 g of 3,4-dihydro-1-benzoxepin-5 (2H) -one oxime. Melting point 96-98 ° C.

b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5 (2H) -one oxime in 15 ml of 1,2-dimethoxyethane (DME) at 0 ° C for 20 minutes dropwise under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borate in 50 ml of 1,2-dimethoxyethane. After stirring at room temperature for 2 days, 100 ml of water was added dropwise and the pH of the mixture was made alkaline with concentrated ammonia solution. After filtering off the precipitate, the filtrate was extracted three times with ethyl acetate. After washing with brine, drying over magnesium sulfate and evaporation, 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-

Of 1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of tetrahydrofuran was added dropwise 0.86 g (6.7 mmol) of ethanesulfonic acid chloride under ice-cooling. The mixture was allowed to warm to room temperature, stirred overnight, and then the solvent was distilled off in vacuo. After stirring the residue with water, the precipitated product is filtered off. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-terahydro-1-benzoxepine are obtained. Melting point 109-111 ° C.

Μ

d) To a suspension of 0.16 g (5.4 mmol) of 80% sodium hydride in 10 ml of tetrahydrofuran under nitrogen is added dropwise a solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro of 1-benzoxepine in 15 ml of tetrahydrofuran. After stirring at room temperature for 3 hours, 1.6 g (11 mmol) of methyl iodide is added dropwise and the mixture is stirred at room temperature overnight. After distilling off the solvent, the residue was mixed with water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated in vacuo. 1.0 g of 5- (N-ethylsulfonyl-N-methylamino) -2,3,4,5-tetrahydro-1-benzoxepine is obtained. Melting point 122-124 ° C.

Example 7

5- (N-butyl-N-ethylsulfonyl-amino) -2,3,4,5-tetrahydro-l-benzoxepin)

7.1 g of 5-ethylsulfonylamino) -2,3,4,5-tetrahydrobenzoxepine (Example 6 c) were prepared by analogous alkylation to Example 11 but with butyl iodide. 8.3 g of 5- (N-butyl-N-ethylsulfonylamino) -2,3,4,5-tetrahydro-1-benzoxepine are obtained as a viscous oil which crystallizes after a long time. Melting point 62-65 ° C.

Example 8

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

°. · Z

with.

* ~~ N * O

a) To a solution of 2.0 g (12.2 mmol) of 5-amino-2,3,4,5-terahydro-1-benzoxepine (Example 6b) and 3.7 g (36.6 mmol) of triethylamine in 40 ml tetrahydrofuran was added dropwise while cooling with ice, 1.54 g (13.4 mmol) of methanesulfonic acid chloride, allowed to come to room temperature, stirred overnight, treated with 50 ml of water, and then tetrahydrofuran was distilled off in vacuo. 50 ml of water are added, the mixture is stirred for 3 hours and the precipitated product is filtered off with suction, dried in vacuo to give 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine, m.p. C.

b) To a suspension of 0.23 g (6.2 mmol) of 80% sodium hydride in 10 ml of tetrahydrofuran is added dropwise a solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro of 1-benzoxepine in 15 ml of tetrahydrofuran. After two hours at room temperature, iodomethane (0.94 g, 6.7 mmol) was added and the mixture was stirred again at room temperature overnight. After distilling off the solvent in vacuo, the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid and water. It is then dried over magnesium sulphate and evaporated. Subsequent recrystallization of the product from isopropanol gave 0.5 g of 5- (N-methyl-N-methylsulfonylamino) -2,3,4,5-terahydro-1-benzoxepine. M.p .: 143-145 ° C.

Example 9

5- (N-butyl-N-methylsulphonyl-amino) -2,3,4,5-tetrahydro-l-benzoxepin

1.0 g of 5-methylsulfonylamino-2,3,4,5-terahydro-1-benzoxepine (Example 8a) was subjected to a reaction analogous to that of Example 11 with sodium hydride and iodobutane in dimethylformamide. Recrystallization of the crude product (1.0 g) from isopropanol gave 0.4 g of 5- (N-butyl-N-methylsulfonylamino) -2,3,4,5-tetrahydro-1-benzoxepine. Melting point: 78 - 79 ° C.

Example 10

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

a) A mixture of 90 g of 4- (4-chloro-2-methylphenoxy) butyric acid (Aldrich) and 1000 g of polyphosphoric acid was stirred at 85 ° C for 4.5 hours. It is then poured into 5 liters of ice water, stirred for 1 hour, and then extracted with ether. The combined organic phases are washed several times with a solution of soda and water, dried over magnesium sulphate and evaporated. The dark residue is then taken up in ether and boiled several times with activated carbon and silica gel and filtered until the solution is only slightly colored. Evaporation gave 48.4 g of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one, m.p. 56-58 ° C.

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 cyanoborohydrin are stirred for 5 hours. hours at 60 ° C and then 2 days at room temperature. The reaction mixture is then acidified with hydrochloric acid and evaporated on a rotary evaporator. The residue is taken up in water, the pH is made alkaline with ammonia solution and extracted with ethyl acetate. After drying and evaporation, the residue is chromatographed on silica gel (ethyl acetate / methanol 9: 1) to give 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine .

c) To 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 tetrahydrofuran is added dropwise with ice-cooling, 86 g of ethanesulfonic acid chloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent is distilled off under vacuum, the residue is mixed with water and the precipitated product is filtered off with suction and dried under vacuum. 1.6 g of 7-chloro-9-methyl-5- (N-ethylsulfonylamino) -2,3,4,5-tetrahydro-1-benzoxepine are obtained, m.p. 144-145 ° C.

d) To a suspension of 0.1 g (2.7 mmol) of 80% sodium hydride in 5 ml of tetrahydrofuran was added dropwise a solution of 0.6 g (2.0 mmol) of 7-chloro-9-methyl-5- (N-) under nitrogen. ethylsulfonylamino) -2,3,4,5-tetrahydro-1-benzoxepine in 8 mL of tetrahydrofuran. After stirring at room temperature for one hour, 0.41 g (2.9 mmol) of methyl iodide is added dropwise and stirred overnight at room temperature. After distilling off the solvent, the residue was mixed with water and extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid and water, it is dried over magnesium sulphate, evaporated in vacuo and the crude product recrystallized from methylene chloride. 0.4 g is obtained

7-chloro-9-methyl-5- (N-ethylsulfonyl-N-amino) -2,3,4,5-tetrahydro-1-benzoxepine, m.p. 141-143 ° C.

¹ H-NMR (CDC1 _3): delta [ppm] = 1.35 (3H), 1.9 to 2.2 (4H), 2.2 (3H), 2.9 (3H), 3.05 ( 2H), 3.7 (1H), 4.2 (1H), 5.15 (1H), 7.1 (2H).

Example 11

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

A solution of 0.8 g (2.6 mmol) of 7-chloro-9-methyl- (N-ethylsulfonylamino) -2 is added dropwise to a suspension of 0.1 g (2.7 mmol) of 80% sodium hydride in 8 ml of dimethylformamide under nitrogen. 3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 mL of dimethylformamide. After 30 min. With stirring at room temperature, 0.96 g (3.7 mmol) of butyl iodide are added dropwise and the mixture is stirred overnight at room temperature. After distilling off the solvent, the residue was stirred with water and extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid and water and drying over magnesium sulphate, it is evaporated under vacuum. 0.9 g of 5- (N-butyl-N-ethylsulfonylamino) -7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine is obtained, m.p. 83-87 ° C.

Example 12

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

0.6 g of 5-amino-7-chloro-9-methyl-2,3,4,5-terahydro-1-benzoxepine (Example 10b) was reacted analogously to Example 10c with methanesulfonic acid chloride. 0.6 g of 7-chloro-9-methyl-5-methylsulfonylamino-2,3,4,5-terahydro-1-benzoxepine is obtained, m.p. 154-156 ° C. Subsequent alkylation with butyl iodide analogously to Example 11 affords 0.6 g of 5- (N-butyl-N).

(methylsulfonylamino) -7-chloro-9-methyl-2,3,4,5-terahydro-1-benzoxepine, m.p. 106-110 ° C.

Example 13

5- (N-Butyl-N-methylsulfonyl-amino) -7-nitro-2,3,4,5-terahydro-1-benzoxepine

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 transferred to 80 ml of concentrated sulfuric acid during ice-cooling. 5.77 g (67.9 mmol) of sodium nitrate are then added and the mixture is stirred at 0 ° C for 90 minutes. The reaction mixture is poured into 800 ml of ice-water, the precipitated product is filtered off with suction, washed neutral and evaporated in vacuo. After recrystallization from isopropanol, 7 g of 3,4-dihydro-7-nitro-1-benzoxepin-5 (2H) -one is obtained, which is contaminated with about 12% of the corresponding 7,9-dinitro compound. Melting point: 112-116 ° C.

b) 3.4 g (16.4 mmol) of 3,4-dihydro-7-nitro-1-benzoxepin-5 (2H) -one were stirred at 60 ° C for 3 hours with 12.7 g (164 mmol) of acetate ammonium chloride and 7.2 g (115 mmol) of sodium cyanoborohydrin in 55 ml of methanol. After addition of 10 ml of water, the mixture is evaporated in vacuo and the residue is taken up in ethyl acetate and washed with dilute sodium hydroxide. The ethyl acetate phase is extracted with dilute hydrochloric acid and the pH of the acid phase obtained is adjusted to alkaline with sodium hydroxide. After extraction with ethyl acetate and drying and evaporation of the organic phase, it is obtained

1.7 g of 5-amino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine.

c) 1.9 g of 5-methylsulfonylamino is obtained from 1.6 g of 5-amino-7-nitro-2,3,4,5-tetrahydrol-benzoxepine analogously to Example 8;

7-nitro-2,3,4,5-tetrahydro-l-benzoxepine. Mp 150-151 ° C.

d) From 0.5 g of 5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine, 0.6 g of 5- (N) was obtained by reaction with sodium hydride and iodobutane in dimethylformamide analogously to Example 11. -butyl-N-methylsulfonylamino) -7-nitro-2,3,4,5-terahydro-1-benzoxepine. Melting point: 96 - 98 ° C.

Example 14

7-Butoxy-3,4-dihydro-2H-benzoxepin-5-one

(a) From 4-butoxyphenol, 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one (analogous to 7-propoxy-3, 4-bromobutyric acid), followed by saponification and cyclization in the presence of polyphosphoric acid, is obtained from alkylation. 4-dihydro-2H-1-benzoxepin-5-one (see J. Heterocyclic Chem. 26, 1989, 1547).

b) From 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one, reductive amination with ammonium acetate and sodium cyanoborohydrin followed by reaction with methanesulfonic acid chloride followed by alkylation with butyl iodide affords 7-butoxy-3,4- dihydro-2H-1-benzoxepin-5-one (see Example 13b).

Pharmacological testing

The _sK- channels of humans, rats and guinea pigs were also tested on oocytes of Xenopus amphibians. Xenopus Laevis amphibian oocytes were isolated and defoliated and subsequently injected with in vitro synthesized I _sK- encoding RNA. After 2-8 days of expression of the I _sK- protein, the I _sK- currents · ¹ were measured by the oocyte.

(double microelectrode voltage technique). The _sK channels were also activated by regular 15 second voltage surges of -10 mV. The bath was then rinsed with a solution of the following composition: NaCl 96 mm, KCl 2 mM, CaCl 21.8 mm, MgCl ₂ mm, HEPES 5 mm (titrated NaOH to pH 7.5). These experiments were carried out at room temperature. The following instruments were used for data acquisition and analysis: geneclamp amplifier (Axon Instruments, Foster City, USA), MacLab D / A converter and software (ADInstruments, Castle Hill, Australia). The compounds of the present invention were tested by adding them to the bath solution at various concentrations. The effects of the compounds were calculated as the percent inhibition of the I _sK- current that occurred after the addition of the compound. The data was ultimately extrapolated by Hill's equation, determining the corresponding IC 50 concentration for each compound.

literature:

AE Busch, HG Kopp, S .. Waldegger, I. Samarzija, H. SuEbrich, g. Raber, K. Kunzelmann, JP Ruppersberg and F. Lang, "Inhibition of both exogenously expressed I _sK and endogenous K ⁺ channels in Xenopus oocytes by isosorbide dinitrate, J. Fysiol. 491 (1995), 735-741.

Takumi, H. Ohkubo and S. Nakanichi, "Cloning of a 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 mediate species-specific responses to protein kinase, C.Proc.Natl.Acad.Sci. USA 90 (1993), 11528-11532.

An IC50 value of 3.3 μπιοί / stanov was determined as described for Example 13.

Industrial usability

The compounds of formula (I) and their physiologically acceptable salts selectively inhibit the K ⁺ (cAMP) -channels respectively. I _{PCs -} channels. Due to this property, they can also be used as medicaments in human and veterinary medicine as well as a means for biochemical research, in view of their effect on the potassium channels, as well as for diagnostic purposes, e.g. in the in vitro diagnosis of cellular tissue disorders. Furthermore, as mentioned above, they can be used as intermediates for the preparation of other medicaments.

Claims (20)

PATENT CLAIMS Compounds of formula I (D) wherein: X ¹ is -O-, -S-, -SO-, -SO ² -, -CR ² -, -NR ⁶ -, -CO-, or -CR ^X R ⁷ -, R 1 and R ² are independently hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group ,, 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 H or-C _n H2n-R ^8, wherein one methylene group of C _n H _2n can be replaced by -0-, -CH = CH-, -C = C-, -C0- , -CO-O-, -O-O-, -S-, -SO-, -SO 2 -, -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 is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein the pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino , sulfamoyl, methylsulfonyl and methylsulfonylamino, X ² is -CR ^T R ² - or -CR ² R ¹⁰ or, if X ³ and X ¹ 'is -CR ¹ R ² -, X ² is also -O-, -S-, - S0-, or -SO 2 NR ⁵ -, wherein the radicals R ^1, R ² and R ⁶ are as defined for ^X1, but are independent of the radicals X ^1, R ¹⁰ together with R ^{7 represents a} bond, X ³ is -CR ¹ R ² -, or, if X ² and X ⁴ is a group -CR ² -, X ³ is also a group -0-, -S-, -S0-, a group of -S0 ₂ or NR ⁶ -, wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ , but are independent of the radicals X ¹ , -CR ^X R ² -, -NR ⁶ -, -NR ¹¹ -, -CH (OR ³⁰ ) - or -CR ² R ¹¹ , wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ but are independent of the radicals X ¹ , 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 represents a} bond, Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² - or a nitrogen atom, wherein at least 2 of Y ¹ , Y ² , Y ³ and Y ⁴ may also be nitrogen atoms, R ¹² is independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or an alkyl group containing 1; 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cyano, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, azide, -ZC _m H _2in - R ¹³ - or unsubstituted, nitro phenyl or substituted with or with 2 substituents, fluorine, selected chlorine, from the bromine atom is a trifluoromethyl amino group, an ethyl group, a hydroxyl iodine group, a group, a group, nitro, cyano, methyl methoxy, dimethylamino sulfamoyl, methylsulfonyl sulfonylamino, and methylZ is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, R ( ¹⁴⁾ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, m is 0, 1, 2 3 4 5 or 6, R ¹³ is an atom H, trifluoromethyl, pentafluoro- ethyl group, heptafluoropropyl group, cyclo alkyl group containing 3, 4, 5, 6, 7 or 8 carbon carbon, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, thienyl, or a nitrogen heterocycle containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein the phenyl group, the thienyl group and the nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, R ¹⁰ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ¹⁵ and R ¹⁶ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N (benzyl) -. R ( ^30a) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms, or Y ¹ and Y ² together represent a sulfur atom and Y ³ and Y ⁴ each represent -CR ¹² -, the radicals R ¹² are independent and have the meanings given for Y ¹ , Y ² , Y ³ , Y ⁴ , .. Ρι. . R ³ is a group R ¹⁷ -CxH ² xN ¹⁸ - or R ¹⁷ -CxH ₂ -, wherein one methylene group C _x H _{2 -} may be replaced by -O-, -CO-, -S-, -SO-, -SO ₂ or -NR ¹⁹ -, R ¹⁹ is a hydrogen atom, a methyl group or an ethyl group, R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, trifluoromethyl, pentafluoroethyl or heptafluoropropyl, x is 0, 1, 2, 3, 4, 5, 6 , 7, 8, 9, or 10, R is a hydrogen atom or an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or 18 17 R and R together represent a bond unless x is less than 3, or R ³ is phenyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl amino, ethyl, sulfamoyl sulfonylamino, nitro, cyano hydroxyl, methyl methoxy a group, a dimethylamino group, a methylsulfonyl group. group, group, group, group, methyl or R ³ and R ⁴ together represent or 8 atoms an alkylene chain of carbon, wherein the alkylene chain may be 3, 4, one methylene replaced by -O-, 5, 6, 7 is -CO-, -S-, -SO-, or -S0 ₂ -, R ⁴ It is C _y H _2y -R ^20, wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CH = CH-, -C? C- group, -C0- group, a group -C0-0- , -O-CO-, -S-, -SO-, -SO ₂ -, -NR ²¹ -, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 R ²⁰ is hydrogen, methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -NR ²² R ²³ , phenyl, thienyl or nitrogen containing heterocycle 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromo, iodo, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino, R ²² and R ²³ 'are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ( ²²⁾ and R ( ²³⁾ together are a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH3) - or -N (benzyl) - . R ⁵ is a hydrogen atom or together with Ŕ ¹¹ represents a bond, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts. Compounds of formula I according to claim 1, wherein X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ , R ⁴ and R ⁵ are as defined in claim 1, but both R ³ and R ⁴ are other than hydrogen in all their stereoisomeric forms, and their mixtures of any ratio, as well as their physiologically acceptable salts. Third Compounds according to claim 1 and / or 2, in which: X ¹ is -O-, -S-, -CR ¹ R ² -, or -SO ₂ -, -SO ₂ -, -NR ⁶ -, R ¹ R ² are independently hydrogen, trifluoromethyl pentafluoroethyl, heptafluoropropyl alkyl containing 1, 2, 3, 4, 5 or a group, group, carbon atom or phenyl unsubstituted substituted by 1 or 2 substituents, from the group consisting of fluorine, chlorine , bromine atom, atom or iodine, trifluoromethyl amino group, nitro group, cyano group, hydroxyl group, methyl methoxy group, dimethylamino sulfamoyl group, methylsulfonyl group ethyl group, group, methylsulfonylamino group, or R ¹ and R ² together represent an alkylene chain containing 2, 6, 7, 8, 9 or 10 carbon atoms, 3 4, 5, R ⁶ is hydrogen or -C _n H 2 _n -R ⁸ -, wherein one methylene group of C _{n H 2n} may be replaced by -O-, -CH = CH-, -C = C-, -CO- , -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ -, -NR ⁹ -, or -CONR ⁹ -, R ⁹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, R ⁸ is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazine - 1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein the pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, X ² is a group -CR ² -, wherein the radicals R ¹ and R ² are as defined for ^X1, but are independent of the radicals X ^1, X ³ is -CR ^X R ² -, wherein R ¹ and R ² are as defined at X ¹ but are independent of X ¹ , X ⁴ is CR ^X R ² -, -NR ⁶ -, -NR ¹¹ - or -CH (OR ³⁰ ) -, wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ but are on the radicals X ¹ independent, 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 represents a bond, Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² - or a nitrogen atom, with a maximum of 2 groups of Y ¹ , Y ² , Y ³ and Y ^{4 being} simultaneously a nitrogen atom, R ¹² is independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cyano , trifluoromethyl, pentafluoroethyl, heptafluoropropyl group, an azide group, a nitro group, a group ZC _m H 2 ^_ _m R ¹³ or a phenyl group unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, FROM is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ -, -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, R ¹⁴ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, m is 0, 1, 2, 3, 4, 5 or 6, R ¹³ is hydrogen, trifluoromethyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, thienyl or nitrogen containing 1, 2 , 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine atom, trifluoromethyl amino group, ethyl group, nitro group, cyano hydroxyl group, methyl methoxy group, dimethylamino group, group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, R ¹⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ( ¹⁵⁾ and R ( ¹⁶⁾ together are a chain of 4 or 5 methylene groups, of which one can -S-, -NH-, -N (benzyl) -, be replaced by -O-, group group -N (CH ₃₎ - or _R ³ ° a is hydrogen, alkyl containing 1, carbon or acyl containing 2 or 1, 2, 3 3 atoms or 4 carbon atoms; or Y ¹ and Y ² together represent a sulfur atom and Y ³ and Y ⁴ are each -CR ¹² -, the radicals R ¹² are independent and defined at Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ is R ¹⁷ ~ CxH2xNR ¹⁸ - or R ¹⁷ -CxH ₂ -, wherein one methylene group of the group C _x H _2x can be replaced by -0-, -C0- group, -S-, -S0- , group. -SO ₂ - or -NR ¹⁹ -, I R ¹⁹ is hydrogen, methyl or ethyl, R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, trifluoromethyl, pentafluoroethyl or C 3 F 7, x is a 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. R ¹⁸ is a a hydrogen atom or an alkyl group containing 1, 2, 3, 4. 5, 6, 7 or 8 carbon atoms, or R ¹⁸ and R ¹⁷ together represent a bond unless x is less than 3, or R ³ is phenyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl , methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, or R ³ and R ⁴ together represent an alkylene chain containing 3, 4, 5, 6, 7 or 8 carbon atoms, one methylene group of the alkylene chain being replaced by -O-, -CO-, -S-, -S- SO- or -so ₂ -, R ⁴ is C _y H _2y -R ^20, wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CH = CH-, -C = C-, -C0-, by - CO-O-, -O-CO-, -S-, -SO-, -SO ₂ -, -NR ²¹ - or -CONR ²¹ -, R ²¹ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5, 6 7 8 9 10 11 12 13 14 15 16, 17, 18, 19 or 20 R ²⁰ is hydrogen, methyl a trifluoromethyl group, pentafluoroethyl, C3F7, cycloalkyl, having 3, 4, 5 or 6 carbon atoms, -NR ²² R ^23, phenyl, thienyl or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycles are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino a hydroxyl group, a methyl group, an ethyl group, a methoxy group, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group, R ²² and R ²³ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ² and R ²³ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH 3) - or -N (benzyl) -. R ⁵ is a hydrogen atom or together with R ¹¹ represents a bond, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts. Compounds of formula I according to one or more of claims 1 to 3, in which: X ¹ is -O-, -S-, -SO-, -SO ₂ -, -CR ¹ R ² -, -NR ⁶ -, R ¹ and R ² are independently hydrogen, trifluoromethyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or R ¹ and R ² together are an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, R ⁶ is H or-C _n H _2n ^- wherein R ^{8 is} R, one methylene group _CnH2n can be replaced by -0-, -CH = CH-, -C? C-, -CO- , -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ -, -NR ⁹ -, or -CONR ⁹ -, R ⁹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, R ⁸ * is hydrogen, trifluoromethyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, dimethylamino, diethylamino, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl, imidazolyl or phenyl, wherein the pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, and methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, x ² is -CR ¹ R ² -, wherein R ¹ and R ² are as defined at X ¹ but are independent of X ¹ , x ³ is -CR ¹ R ² -, wherein R ¹ and R ² are as defined at X ¹ but are independent of X ¹ , x ⁴ is CR ¹ R ² -, -NR ⁶ -, -NR ¹¹ - or -CH (OR ³⁰ ) -, wherein the radicals R ¹ , R ² and R ⁶ are as defined at X ¹ but are on the radicals X ¹ independent, 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 represents a bond, Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ¹² - R ¹² is independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, cyano, trifluoromethyl, a pentafluoroethyl group, a heptafluoropropyl group, an N ₃ group, a nitro group, a -ZC _m H 2 _m -R ¹³ group or a phenyl group which is unsubstituted or substituted by 1 or 2 substituents, from the group consisting of fluorine, chlorine, bromine, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, FROM is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, R ¹⁴ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, m is 0, 1, 2, 3, 4, 5 or 6, R ¹³ is hydrogen, trifluoromethyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, thienyl or nitrogen containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 ΊΟ or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy, dimethylamino, sulfamoyl a methylsulfonyl group and a methylsulfonylamino group, R ¹⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ¹⁵ and R ¹⁶ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N (benzyl) -. R ( ^30a) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms, or Y ¹ and Y ² together represent a sulfur atom and each of Y ³ and Y ⁴ is -CR ¹² -, the radicals R ¹² are independent and defined at Y ¹ , Y ² , Y ³ , Y ⁴ , R ³ is R ¹⁷ -CxH ² x NR ¹⁸ - or * R ¹⁷ -CxH ₂ -, wherein one methylene group of C _x H _{2 -} may be replaced by -O-, -CO-, -S-, -SO -, -SO ₂ - or -NR ¹⁹ -, R ¹⁹ is a hydrogen atom, a methyl group or an ethyl group, R ¹⁷ is hydrogen, methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, trifluoromethyl, pentafluoroethyl or heptafluoropropyl, x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R ¹⁸ is a hydrogen atom or an alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or R ^x and R ^x together represent a bond unless x is less than 3. or R ³ is a phenyl group unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, amino, hydroxyl, methyl, ethyl, methoxy a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group, R ⁴ It is C _r H 2 _N ^- R ²⁰ / wherein one methylene group of the group C _r H _2r can be replaced by -0-, -CH = CH-, -C = C-, -C0-, group -C0- O-, -O-CO-, -S-, -SO-, -SO2-, -NR ²¹ -, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5, 7, 8, 9 or 10, R ²⁰ is methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, -NR ²² R ²³ , phenyl, thienyl or nitrogen containing 1, 2, 3, 4 , 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, thienyl and nitrogen heterocycle are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, nitro group, cyano group, amino group, hydroxyl group, methyl group, ethyl group, methoxy group, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, R ²² and R ²³ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or R ( ²²⁾ and R ( ²³⁾ together are a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -N (CH ₃ ) - or -S-, by a group -NH-, a group by a group -N (benzyl) R ⁵ is a hydrogen atom or together with R ¹¹ represents a bond, in all of its proportions, forms and their stereoisomeric as well as their physiologically acceptable salt mixtures. Compounds of formula I according to one or more of claims 1 to 4, in which: X ¹ is -O- or -CR ^X R ² -, R ¹ and R ² are independently hydrogen, trifluoromethyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,. ' X ² is -CR ¹ R ² -, wherein R ¹ and R ² are as defined in X ¹ , but are independent of X ¹ residues, X ³ is -CR ^X R ² -, wherein R ¹ and R ² are as defined in X ¹ , but are independent of X ¹ residues, X ⁴ is CR ^X R ² - or -CH (OR ³⁰ ) -, with residues R ¹ and R ² are defined at X ¹ but are independent of the X ¹ radicals, R ( ³⁰⁾ is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms, Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ^12, R ¹² are independently hydrogen, fluorine, chlorine, bromine, iodine, alkyl containing 1, 2, 3, 4 or 5 carbon atoms, a cyano group, a trifluoromethyl group, a nitro group, a -ZC _m H _2ra -R ¹³ group or a phenyl group unsubstituted or substituted With 1 or 2 substituents, fluorine, chlorine, bromine, trifluoromethyl amino, ethyl, hydroxy, methoxy, nitro, cyano, methyl dimethylamino iodo, sulfamoyl a methylsulfonyl group and a methylsulfonylamino group, Z is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, R ¹⁴ is hydrogen or alkyl having 1, 2 or 3 carbon atoms is 0, 1, 2 or 3, R ¹³ is a thienyl group 1,2,3 hydrogen, trifluoromethyl, -NR ¹⁵ R ¹⁶ , -CONR ¹⁵ R ¹⁶ , -OR ^30a , phenyl, or a nitrogen-containing heterocycle containing 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the group, thienyl or nitrogen is unsubstituted or substituted by 1 phenyl heterocycle or 2 fluorine, chlorine, bromine, trifluoromethyl amino, ethyl, hydroxyl methoxy, nitro , cyano, methyl dimethylamino iodine, group, group, group, methyl74 sulfamoyl, methylsulfonyl and sulfonylamino, R ¹⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, or: R ¹⁵ and R ¹⁶ together represent a chain of 4 or 5 methylene groups, one of which may be replaced by -O-, -S-, -NH-, -N (CH ₃ ) - or -N (benzyl) -. R ( ^30a) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms, R ³ is a group R ¹⁷ -C _x H _2x -, R ¹⁷ is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms or trifluoromethyl, x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R ⁴ is C _y H _2y -R ^Q2, wherein one methylene group of the group C _r H _2r can be replaced by -0-, a group -C0-0-, -0-C0- group, -NR ²¹ -, or -CONR ²¹ -, R ²¹ is hydrogen or alkyl having 1, 2 or 3 carbon atoms; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R is methyl, trifluoromethyl or cycloalkyl having 3, 4, 5 or 6 carbon atoms, R ⁵ is hydrogen, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts. Compounds of formula I according to one or more of claims 1 to 5, in which: X ¹ is -O- or -CH ₂ -, X ² is -CR 1 R ² -, R ¹ and R ² are independently hydrogen or alkyl having 1, 2, or 3 carbon atoms, X ³ is methylene or -C (CH ₃ ) ₂ -, X ⁴ is a methylene group or a -CHOH- group, Y ¹ , Y ² , Y ³ and Y ⁴ are independently -CR ^12, R ¹² are independently hydrogen, fluoro, chloro, bromo, alkyl having 1, 2 or 3 carbon atoms, cyano, trifluoromethyl, nitro group, -ZC _m H ₂ ni-R ¹³ - group, Z is -O-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO ₂ - or -SO ₂ NR ¹⁴ -, -NR ¹⁴ - or -CONR ¹⁴ -, R ¹⁴ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, m is 0, 1, 2 or 3; R ¹³ is hydrogen, trifluoromethyl, -NR ¹⁵ R ¹⁶ , phenyl, piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl or imidazolyl, R ¹⁵ and R ¹⁶ are independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, R ³ is a ^R17-C _x H _2x,. R ¹⁷ is a methyl, x is a 0, 1, 2 or 3 R ⁴ is a group C _r H _2r -R ^20, with one methylene group the group C _r H _2r may be replaced by -O-, group -CO-O-, -O-CO-, -NR- ^21- or -CONR- ^21- , R ²¹ is hydrogen or alkyl having 1, 2 or 3 carbon atoms, r is 0, 1, 2, 3, 4, 5 or 6, R ²⁰ is methyl, trifluoromethyl or pyridyl, R ⁵ is hydrogen, in all its stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts. Compounds of formula I according to one or more of claims 1 to 5, in which: X ¹ is -O-, X ² is -CR 1 R ² -, R ¹ and R ² are independently hydrogen, an alkyl group containing 1, 2, or 3 atoms alkyl, X ³ is methylene group or group X ⁴ is methylene group, Y ¹ is CH, Y ² is CH, Y ⁴ is CH, Y ³ is -CR ¹² -, R ¹² is fluorine, chlorine, bromine, alkyl or 3 carbon atoms, cyano, nitro, 1,2-trifluoromethyl-ZC ₁ H _2m -R ¹³ -, group -O-, group -CO-, -CO-O-, group R ¹⁴ -O-CO-, -SO ₂ NR ¹⁴ -s-, or -SO-, -SO ₂ - or -CONR ¹⁴ -, is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, m is 1, 2 or 3, R ¹³ is hydrogen, trifluoromethyl, pyridyl or phenyl, R ³ is R ¹⁷ -C _x H _2x -, R ¹⁷ is methyl, x is 0, 1 or 2 R ⁴ a group 'C _y H _2y -R ^20, wherein one methylene group of the group C _r H _2r can be replaced by -0-, a group -C0-0-, -0-C0- group, or -CONR ²¹ -, R ²¹ is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms, · r is 0, 1, 2, 3, 4, 5 or 6, R ²⁰ is methyl or trifluoromethyl, R ⁵ is hydrogen, in all their stereoisomeric forms and mixtures thereof in any ratio, as well as their physiologically acceptable salts. Compounds of formula I according to one or more of claims 1 to 7 and their physiologically acceptable salts for use as medicaments. A pharmaceutical composition comprising an effective amount of at least one compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof together with pharmaceutically acceptable carriers and additives, and optionally another one or more pharmaceutically active substances. Use of a compound according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament with a K ⁺ -channel blocking effect for the treatment and prophylaxis of K ⁺ -channel related diseases. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for inhibiting gastric acid secretion. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of gastric ulcer or gastrointestinal ulcer. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of reflux esophagitis. I. ’·, Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of diarrhea. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of all types of arrhythmias including atrial, ventricular and supraventricular arrhythmias. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of cardiac rhythm disorders which can be eliminated by prolonging the action potential. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of atrial fibrillation or atrial oscillation. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of reentry arrhythmias or for preventing sudden cardiac death due to ventricular oscillation. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment of cardiac insufficiency. Use of a compound of formula I according to one or more of claims 1 to 7 and / or a physiologically acceptable salt thereof for the preparation of a medicament for inhibiting stimulated gastric acid secretion, for the treatment or prophylaxis of gastric or digestive ulcers, reflux esophagitis, diarrhea, or prophylaxis of arrhythmias including atrial, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial oscillation and reentry arrhythmias, or to prevent sudden cardiac death due to ventricular oscillation.