Field of the Invention
The invention relates to compounds of the formula I ##STR2## in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(9), and B have the meanings indicated below, their preparation and their use, in particular in pharmaceuticals. The compounds affect the potassium channel opened by cyclic adenosine monophosphate (cAMP) or the I.sub.Ks channel and are outstandingly suitable as pharmaceutical active compounds, for example for the prophylaxis and therapy of cardiovascular disorders, in particular arrhythmias, for the treatment of ulcers of the gastrointestinal area or for the treatment of diarrheal disorders.
In pharmaceutical chemistry, in recent years the 4-acylaminochroman derivatives class has been worked on intensively. The most prominent representative of this class is cromakalim of the formula A (J. Med. Chem. 1986, 29, 2194). ##STR3##
Cromakalim and other related 4-acylaminochroman derivatives are compounds having a relaxant action on smooth muscular organs, so they are used for lowering raised blood pressure as a result of vascular muscle relaxation and in the treatment of asthma as a result of relaxation of the smooth musculature of the airways. It is common to all these preparations that they act at the cellular level, for example, of smooth muscle cells and result there in an opening of certain ATP-sensitive K.sup.+ channels. The increase in negative charge in the cell (hyperpolarization) induced by the efflux of K.sup.+ ions counteracts the increase in the intracellular Ca.sup.2+ concentration via secondary mechanisms and thus cell activation, which leads, for example, to muscle contraction.
The compounds of the formula I according to the invention differ from these acylamino derivatives structurally, inter alia, by the replacement of the acylamino group by a sulfonylamino function. While cromakalim (formula A) and analogous acylamino compounds act as openers of ATP-sensitive K.sup.+ channels, the compounds of the formula I according to the invention having the sulfonylamino structure, however, do not show any opening action on this K.sup.+ (ATP) channel, but surprisingly show a strong and specific blocking (closing) action on a K.sup.+ channel which is opened by cyclic adenosine monophosphate (cAMP) and differs fundamentally from the K.sup.+ (ATP) channel mentioned. More recent investigations show that this K.sup.+ (cAMP) channel identified in colonic tissue is very similar, perhaps even identical, to the I.sub.Ks channel identified in the cardiac muscles. In fact, it was possible for the compounds of the formula I according to the invention to show a strong blocking action on the I.sub.Ks channel in guinea-pig cardiomyocytes and also on the I.sub.sK channel expressed in Xenopus oocytes. As a result of this blocking of the K.sup.+ (cAMP) channel or of the I.sub.Ks channel, the compounds according to the invention display pharmacological actions of high therapeutic utility in the living body.
Apart from the abovementioned cromakalim or acylaminochroman derivatives, compounds having a 4-sulfonylaminochroman structure, which, however, differ markedly from the compounds of the formula I according to the invention both in the structure and in the biological action, are also described in the literature. Thus EP-A-315 009 describes chroman derivates having a 4-phenylsulfonylamino structure, which are distinguished by antithrombotic and antiallergic properties. EP-A-389 861 and JP 01294677 describe 3-hydroxychroman or chromene derivatives having a cyclic 4-sulfonylamino group (e.g., compound B), which should act as antihypertensives via activation of the K.sup.+ (ATP) channels. EP-A-370 901 describes 3-hydroxychroman or chromene derivatives having a 4-sulfonylamino group, the remaining valency of the N atom bearing a hydrogen atom, which have CNS actions. Further, 4-sulfonylaminochroman derivatives are described in Bioorg. Med. Chem. Lett. 4 (1994), 769-773: "N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburyde insensitive smooth muscle relaxants to potent smooth muscle contractors" and in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating I.sub.sK channels by chromanols . . . " and Pflugers Arch.--Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-mediated Cl.sup.- secretion in rabbit colon, acting by the reduction of cAMP-activated K.sup.+ conductance". ##STR4##
The present invention relates to compounds of the formula I ##STR5## in which: R(1) and R(2)
independently of one another are hydrogen, CF.sub.3, C.sub.2 F.sub.5, C.sub.3 F.sub.7, alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, or phenyl, PA2 where one CH.sub.2 group in the groups C.sub.n H.sub.2n can be replaced by --O--, --CO--, --S--, --SO--, --SO.sub.2 --, or --NR(12a)--; PA2 R(10) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, CF.sub.3, C.sub.2 F.sub.5, or C.sub.3 F.sub.7 ; PA2 n is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; PA2 R(11) is hydrogen or alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or PA2 R(10) and R(11) together are a bond, provided n is not smaller than 3; PA2 q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; PA2 r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; PA2 Z is --CO--NR(14)--, PA2 --C.sub.y H.sub.2y --OR(12b), --C.sub.y H.sub.2y --NR(12b).sub.2 ; PA2 R(13) is H, CF.sub.3, C.sub.2 F.sub.5, C.sub.3 F.sub.7, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, --NR(15)R(16), --CONR(15)R(16), --C(.dbd.NR(17))NR(15)R(16), --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, PA2 independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4, or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, --CN, --CF.sub.3, --C.sub.2 F.sub.5, --C.sub.3 F.sub.7, --N.sub.3, --NO.sub.2, --Y--C.sub.s H.sub.2s --R(18), or phenyl, PA2 together are a bond; PA2 independently of one another are hydrogen, CF.sub.3 or alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or PA2 R(10) is methyl, CF.sub.3 or C.sub.2 F.sub.5 ; PA2 n is zero, 1, or 2; PA2 q is 1, 2, 3, 4, 5, 6, 7, or 8; PA2 r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; PA2 Z is --CO--NR(14)--, PA2 R(13) is H, CF.sub.3, C.sub.2 F.sub.5, C.sub.3 F.sub.7, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, --NR(15)R(16), --CONR(15)R(16), --C(.dbd.NR(17))NR(15)R(16), --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, PA2 R(15) and R(16) PA2 R(17) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA2 independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, 4, or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms, --CN, --CF.sub.3, --C.sub.2 F.sub.5, --C.sub.3 F.sub.7, --NO.sub.2, --Y-- C.sub.s H.sub.2s --R(18), or phenyl, when phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA2 together are a bond; PA2 R(10) is methyl, CF.sub.3, or C.sub.2 F.sub.5 ; PA2 n is zero, 1, or 2; PA2 q is 1, 2, 3, or 4; PA2 r is 0, 1, 2, or 3; PA2 Z is --CO--NR(14)--, PA2 R(13) is CH.sub.3, CF.sub.3, C.sub.2 F.sub.5, cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms, --NR(15)R(16), --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, where phenyl and the N-containing heterocycle is unsubstituted or substituted by 1 or 2 substituents, which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; PA2 independently of one another are hydrogen, F, Cl, Br, alkyl having 1, 2, 3, 4, or 5 carbon atoms, cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms, --CN, --CF.sub.3, --C.sub.2 F.sub.5, --NO.sub.2, --Y--C.sub.s H.sub.2s -- R(18), or phenyl, where phenyl is unsubstituted or substituted by 1 or 2 substituents, which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; PA2 are hydrogen; PA2 R(10d) is hydrogen or methyl; PA2 together form a bond; PA2 q is 1, 2, 3, or 4; PA2 r is 0, 1, 2, or 3; PA2 Z is --CO--NR(14)--, PA2 R(13) is CH.sub.3, CF.sub.3, --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, where phenyl and the N-containing heterocycle are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, or methylsulfonylamino; PA2 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, or methylsulfonylamino; PA2 Y is --O--, --CO--, or --CONR(10c)--; PA2 s is 1, 2, 3, 4, or 5; PA2 R(18) is hydrogen, CF.sub.3, or phenyl, PA2 q is 1, 2, 3, or 4; PA2 r is 0, 1, 2, or 3; PA2 Z is --CO--NR(14)--, PA2 R(13) is CH.sub.3, CF.sub.3, --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, PA2 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA2 Y is --O--, --CO--, or --CONR(10c)--; PA2 s is 1, 2, 3, 4, or 5; PA2 R(18) is hydrogen, CF.sub.3, or phenyl, PA2 q is 1, 2, 3, or 4; PA2 r is 0, 1, 2, or 3; PA2 Z is --CO--NR(14)--, PA2 R(13) is CH.sub.3, CF.sub.3, --OR(17), --COOR(17), phenyl, or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, PA2 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, or methylsulfonylamino; PA2 Y is --O--, --CO--, or --CONR(10c)--; PA2 s is 1, 2, 3, 4, or 5; PA2 R(18) is hydrogen, CF.sub.3, or phenyl, PA2 in which R(4) and L have the meanings indicated above; or by
where phenyl is unsubstituted or substituted by 1 or 2 substituents, which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; or PA3 R(12a) is hydrogen, methyl, or ethyl; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --O--, PA3 --O--C.sub.x H.sub.2x --NR(14)--, PA3 --O--C.sub.x H.sub.2x --CO--, PA3 --CO--O--C.sub.x H.sub.2x --O-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--, PA4 where Z may be linked in the forward or reverse directions. PA4 x is 2, 3, or 4; PA3 R(14) is hydrogen, alkyl having 1, 2, or 3 carbon atoms, PA3 R(12b) is hydrogen, methyl, or ethyl; PA3 y is 2 or 3; PA3 where phenyl and the N-containing heterocycle is unsubstituted or substituted by 1 or 2 substituents, which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; PA3 R(15) and R(16) PA4 independently of one another are hydrogen, alkyl having 1,2,3, or 4 carbon atoms or --C.sub.z H.sub.2z -phenyl, PA4 z is zero, 1, or 2; PA4 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; or PA3 R(15) and R(16) PA4 together are a chain of 4 or 5 methylene groups, of which one CH.sub.2 group can be replaced by --O--, --S--, --NH--, --N(CH.sub.3)--, or --N(benzyl)--; PA3 R(17) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA3 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA3 Y is --O--, --CO--, --CO--O--, --O--CO--, --S--, --SO--, --SO.sub.2 --, --SO.sub.2 --O--, --SO.sub.2 NR(10c), --NR(10c)--, or --CONR(10c)--; PA4 R(10c) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA3 s is zero, 1, 2, 3, 4, 5, or 6; PA3 R(18) is hydrogen, CF.sub.3, C.sub.2 F.sub.5, C.sub.3 F.sub.7, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, --COOR(21), 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, thienyl, imidazolyl, quinolyl, isoquinolyl, or phenyl, PA4 where pyridyl, thienyl, imidazolyl, quinolyl, isoquinolyl, and phenyl are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA4 R(21) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --O--, PA3 --O--C.sub.x H.sub.2x --NR(14)--, PA3 --O--C.sub.x H.sub.2x --CO--O, PA3 --CO--O--C.sub.x H.sub.2x --O-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--, PA4 where Z may be linked in the forward or reverse directions; PA4 x is 2, 3, or 4; PA3 R(14) is hydrogen, alkyl having 1, 2, or 3 carbon atoms, C.sub.y H.sub.2y --OR(12b), --C.sub.y H.sub.2y --NR(12b).sub.2 ; PA4 R(12b) is hydrogen, methyl, or ethyl; PA4 y is 2 or 3; PA3 where phenyl and the N-containing heterocycle is unsubstituted or substituted by 1 or 2 substituents, which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; PA3 R(15) and R(16) PA4 independently of one another are hydrogen, alkyl having 1, 2, 3, or 4 carbon atoms or --C.sub.z H.sub.2z -phenyl, PA4 z is zero, 1, or 2; PA4 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, and methylsulfonylamino; or PA3 together are a chain of 4 or 5 methylene groups, of which one CH.sub.2 group can be replaced by --O--, --S--, --NH--, --N(CH.sub.3)--, or --N(benzyl)--; PA3 Y is --O--, --CO--, --CO--O--, --O--CO--, --S--, --SO--, --SO.sub.2 --, --SO.sub.2 --O--, --SO.sub.2 NR(10c), --NR(10c)--, or --CONR(10c)--; PA4 R(10c) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA3 s is zero, 1, 2, 3, 4, 5, or 6; PA3 R(18) is hydrogen, CF.sub.3, C.sub.2 F.sub.5, C.sub.3 F.sub.7, cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms, --COOR(21), 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, imidazolyl, or phenyl, where pyridyl, imidazolyl, and phenyl are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA4 R(21) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --O--, PA3 --O--C.sub.x H.sub.2x --NR(14)--, PA3 --O--C.sub.x H.sub.2x --CO--O, PA3 --CO--O--C.sub.x H.sub.2x --O-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--, PA4 where Z may be linked in the forward or reverse directions; PA3 x is 2 or 3; PA3 R(14) is hydrogen, alkyl having 1 or 2 carbon atoms; PA3 R(15) and R(16) PA4 independently of one another are hydrogen or alkyl having 1, 2, 3, or 4 carbon atoms; or PA3 R(15) and R(16) PA4 together are a chain of 4 or 5 methylene groups, of which one CH.sub.2 group can be replaced by --O--, --S--, --NH--, --N(CH.sub.3)--, or --N(benzyl)--; PA3 R(17) is hydrogen or alkyl having 1 or 2 carbon atoms; PA3 Y is --O--, --CO--, --SO.sub.2 --, or --CONR(10c)--; PA4 R(10c) is hydrogen or alkyl having 1 or 2 carbon atoms; PA3 s is zero, 1, 2, 3, 4, 5, or 6; PA3 R(18) is hydrogen, CF.sub.3, C.sub.2 F.sub.5, cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl, imidazolyl, or phenyl, where pyridyl, imidazolyl, and phenyl are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --NR(14)-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--; PA4 x is 2 or 3; PA4 R(14) is hydrogen or methyl; PA3 R(17) is hydrogen or alkyl having 1 or 2 carbon atoms; PA3 R(10c) is hydrogen or methyl; PA3 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --NR(14)-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--; PA4 x is 2 or 3; PA4 R(14) is hydrogen or methyl; PA3 where phenyl and the N-containing heterocycle are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, or methylsulfonylamino; PA3 R(17) is hydrogen or alkyl having 1 or 2 carbon atoms; PA3 R(10c) is hydrogen or methyl; PA3 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; PA3 --OCO--NR(14)--, PA3 --O--C.sub.x H.sub.2x --NR(14)-- or PA3 --CO--O--C.sub.x H.sub.2x --NR(14)--; PA4 x is 2 or 3; PA4 R(14) is hydrogen or methyl; PA3 where phenyl and the N-containing heterocycle are unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, aminosulfonyl, or methylsulfonylamino; PA3 R(17) is hydrogen or alkyl having 1 or 2 carbon atoms; PA3 R(10c) is hydrogen or methyl; PA3 where phenyl is unsubstituted or substituted by 1 or 2 substituents which are F, Cl, Br, CF.sub.3, NO.sub.2, CN, NH.sub.2, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl, or methylsulfonylamino;
R(1) and R(2) together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; PA1 R(3) is R(10)--C.sub.n H.sub.2n --NR(11)-- or R(10)--C.sub.n H.sub.2n --, PA1 R(4) is R(13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5), R(6), R(7), and R(8) PA1 R(9) is hydrogen, OR(10d), or OCOR(10d); PA1 R(10d) is hydrogen or alkyl having 1, 2, or 3 carbon atoms; PA1 B is hydrogen; or PA1 R(9) and B PA1 R(1) and R(2) PA1 R(1) and R(2) together are an alkylene chain having 2, 3, 4, 5, or 6 carbon atoms; PA1 R(3) is R(10)--C.sub.n H.sub.2n --; PA1 R(4) is R(13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5), R(6), R(7), and R(8) PA1 R(9) is hydrogen or OR(10d); PA1 R(10d) is hydrogen or methyl; PA1 B is hydrogen; or PA1 R(9) and B PA1 R(1) and R(2) independently of one another are hydrogen, CF.sub.3, or alkyl having 1, 2, or 3 carbon atoms; or PA1 R(1) and R(2) together are an alkylene chain having 2, 3, 4, or 5 carbon atoms; PA1 R(3) is R(10)--C.sub.n H.sub.2n --; PA1 R(4) is R(.sup.13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5) and R(6) PA1 R(7) and R(8) PA1 R(9) is hydrogen or OR(10d); PA1 B is hydrogen; or PA1 R(9) and B PA1 R(1) and R(2) are methyl; PA1 R(3) is methyl or ethyl; PA1 R(4) is R(13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5) is hydrogen, alkyl having 1, 2, 3, or 4 carbon atoms, F, Cl, methoxy, or ethoxy; PA1 R(6) is F, Cl, alkyl having 1, 2, 3, 4, or 5 carbon atoms, --CF.sub.3, --Y--C.sub.s H.sub.2s --R(18), or phenyl, PA1 R(7) and R(8) are hydrogen; PA1 R(9) is hydrogen; PA1 B is hydrogen; PA1 R(1) and R(2) are methyl; PA1 R(3) is methyl or ethyl; PA1 R(4) is R(13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5) is hydrogen, alkyl having 1, 2, 3, or 4 carbon atoms, F, Cl, methoxy, or ethoxy; PA1 R(6) is F, Cl, alkyl having 1, 2, 3, 4, or 5 carbon atoms, --CF.sub.3, --Y-- C.sub.s H.sub.2s --R(18) or phenyl, PA1 R(7) and R(8) are hydrogen; PA1 R(9) is OH; PA1 B is hydrogen; PA1 R(1) and R(2) are methyl; PA1 R(3) is methyl or ethyl; PA1 R(4) is R(13)--C.sub.r H.sub.2r --Z--C.sub.q H.sub.2q --; PA1 R(5) is hydrogen, alkyl having 1, 2, 3, or 4 carbon atoms, F, Cl, methoxy, or ethoxy; PA1 R(6) is F, Cl, alkyl having 1, 2, 3, 4, or 5 carbon atoms, --CF.sub.3, --Y--C.sub.s H.sub.2s --R(18) or phenyl, PA1 R(7) and R(8) are hydrogen; PA1 R(9) and B together are a bond; PA1 a) reacting a compound of the formula II ##STR6## in which R(1), R(2), R(5), R(6), R(7), R(8), and R(9) have the meanings indicated above and L is a nucleofugic leaving group, in particular Cl, Br, I, methanesulfonyloxy, or p-toluenesulfonyloxy, in a manner known per se with a sulfonamide or its salt of the formula III ##STR7## in which R(3) and R(4) have the meanings indicated above and M is hydrogen or preferably a metal equivalent, particularly preferably lithium, sodium, or potassium; or by PA1 b) reacting a compound of the formula IV ##STR8## in which R(1), R(2), R(4), R(5), R(6), R(7), R(8), and R(9) have the meanings indicated above, with a sulfonic acid derivative of the formula V ##STR9## in which R(3) has the meanings indicated above and W is a nucleofugic leaving group, such as, for example, fluorine, bromine, 1-imidazolyl, but in particular chlorine; or by PA1 c) reacting a compound of the formula VI ##STR10## in which R(1), R(2), R(3), R(5), R(6), R(7), R(8), R(9) and M have the meanings indicated above, in a manner known per se in the sense of an alkylation reaction with an alkylating agent of the formula VII, EQU R(4)--L VII PA1 d) carrying out an electrophilic substitution reaction in a compound of the formula I ##STR11## in which R(1) to R(9) and B have the meanings indicated above, in at least one of the positions R(5), R(6), R(7), and R(8), if this position is hydrogen; or by PA1 e) reacting a compound of the formula VIII ##STR12## in which R(1), R(2), R(3), R(5), R(6), R(7), R(8), R(9), q, and B have the meanings indicated above, with a compound of the formula IX , X or XI, ##STR13## in which R(13), R(14), r and x have the meanings indicated above, in the sense of an esterification or amidation reaction; or by PA1 f) reacting a compound of the formula XII ##STR14## in which R(1), R(2), R(3), R(5), R(6), R(7), R(8), R(9), q, and B have the meanings indicated above, with a compound of the formula XIII or XIV ##STR15## in which R(13), R(14), r, x and L have the meanings indicated above, in the sense of an alkylation reaction; or by PA1 g) reacting a compound of the formula XV, ##STR16## in which R(1), R(2), R(5), R(6), R(7), and R(8) have the meanings indicated above, with a sulfonamide of the formula III in which R(3), R(4) and M have the meanings indicated above or M is advantageously also a trialkylsilyl radical, e.g., a trimethylsilyl radical, to give a chromanol of the formula Ia; or by PA1 h) converting a compound of the formula Ia, ##STR17## in which R(1) to R(8) have the meanings indicated above, in the sense of an elimination reaction to give a compound of the formula Ib, in which R(1) to R(8) have the meanings indicated above. PA1 in which R(4) has the meanings indicated, under reductive conditions or reductive catalytic conditions, preferably at relatively elevated temperature and in an autoclave. In this reaction, primarily by condensation reaction of the ketones of the formula XVI (A=oxygen) and the amines of the formula XVII in situ, Schiff bases of the formula XVI in which A is R(4)--N.dbd. are formed which can be converted immediately, i.e. without prior isolation, into the amines of the formula IV by reduction. However, it is also possible to prepare the Schiff bases (formula XVI, A is R(4)--N.dbd.) intermediately formed in the condensation reaction from the compounds of the formulae XVI and XVII according to methods known from the literature and to first isolate them, in order to then convert them in a separate step using a suitable reductant, such as, for example, NaBH.sub.4, LiAlH.sub.4, NaBH.sub.3 CN, or by catalytic hydrogenation in the presence of, for example, Raney nickel or a noble metal such as, for example, palladium, into the compounds of the formula IV. PA1 1. aromatic nitration to introduce one or more nitro groups, some or all of which can be reduced to amino groups in subsequent reactions. The amino groups can in turn be converted into other groups in subsequent reactions, for example in a Sandmeyer reaction, e.g., to introduce cyano groups; PA1 2. aromatic halogenation, in particular to introduce chlorine, bromine or iodine; PA1 3. chlorosulfonation, e.g., by action of chlorosulfonic acid to introduce a chlorosulfonyl group, which can be converted into other groups in subsequent reactions, e.g., into a sulfonamide group; PA1 4. the Friedel-Crafts acylation reaction to introduce an acyl radical or a sulfonyl radical by action of the corresponding acid chlorides in the presence of a Lewis acid as a Friedel-Crafts catalyst, preferably in the presence of anhydrous aluminum chloride.
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which:
and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are also those in which:
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are furthermore those in which:
and their physiologically tolerable salts.
Alkyl radicals and alkylene radicals can be straight-chain or branched. This also applies to the alkylene radicals of the formulae C.sub.r H.sub.2r, C.sub.q H.sub.2q, C.sub.n H.sub.2n, and C.sub.s H.sub.2s. Alkyl radicals and alkylene radicals can also be straight-chain or branched if they are substituted or are contained in other radicals, e.g. in an alkoxy radical or in an alkylmercapto radical or in a fluorinated alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl. The divalent radicals derived from these radicals, e.g., methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc., are examples of alkylene radicals.
N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms are, in particular, the aromatic systems 1-, 2-, or 3-pyrrolyl, 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 1,2,3-triazol-1-, -4-, or 5-yl, 1,2,4-triazol-1-, -3-, or -5-yl, 1-, or 5-tetrazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1,2,3-oxadiazol-4-, or 5-yl, 1,2,4-oxadiazol-3-, or -5-yl, 1,3,4-oxadiazol-2-yl, or -5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 1,3,4-thiadiazol-2-, or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4-, or -5-yl, 2-, 3-, or 4-pyridyl, 2-, 4-, 5-, or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4-, or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl.
Particularly preferred N-containing heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
Thienyl represents both 2- and 3-thienyl.
Monosubstituted phenyl radicals can be substituted in the 2-, 3- or the 4-position, or disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position. The same also applies correspondingly for the N-containing heterocycles or the thiophene radical.
In the case of disubstitution of a radical the substituents can be identical or different.
If the radicals R(1) and R(2) together are an alkylene chain, these radicals with the carbon atom bearing them form a ring which has one carbon atom in common with the 6-membered ring in the formula I, thus a spiro-compound is then present. If R(9) and B together are a bond, a 2H-chromene parent structure is present. If R(10) and R(11) together are a bond, the group R(10)--C.sub.n H.sub.2n --NR(11)-- preferably is a nitrogen heterocycle bonded via a nitrogen atom. If R(10) and R(11) together are a bond and the group R(10)--C.sub.n H.sub.2n --NR(11)-- is a nitrogen heterocycle bonded via a nitrogen atom, this nitrogen heterocycle is preferably a 4-membered ring or a ring larger than a 4-membered ring, e.g., a 5-membered ring, 6-membered ring, or 7-membered ring.
If the compounds of the formula I contain one or more acidic or basic groups or one or more basic heterocycles, the invention also includes the corresponding physiologically or toxicologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus the compounds of the formula I which bear acidic groups, e.g., one or more COOH groups, can be used, for example, as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts, e.g., calcium or magnesium salts, or as ammonium salts, e.g., as salts with ammonia or organic amines or amino acids. Compounds of the formula I which bear one or more basic, i.e., protonatable, groups or contain one or more basic heterocyclic rings can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, etc. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes internal salts, so-called betaines, in addition to the salt forms described. Salts can be obtained from the compounds of the formula I according to customary processes, for example by combination with an acid or base in a solvent or dispersant or alternatively from other salts by anion exchange.
In the case of appropriate substitution, the compounds of the formula I can be present in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these can independently of one another have the S configuration or the R configuration. The invention includes all possible stereoisomers, e.g., enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, e.g., enantiomers and/or diastereomers, in any desired ratios. The invention thus relates to enantiomers, for example, in enantiomerically pure form, both as dextro- and as levorotatory antipodes, and also in the form of mixtures of the two enantiomers in different ratios or in the form of racemates. If cis/trans isomerism is present, the invention relates to both the cis form and the trans form and mixtures of these forms. Individual stereoisomers can be prepared, if desired, by resolution of a mixture according to customary methods or, for example, by stereoselective synthesis. If mobile hydrogen atoms are present, the present invention also includes all tautomeric forms of the compounds of the formula I.
The compounds of the formula I can be prepared by different chemical processes, which are likewise included by the present invention. Thus a compound of the formula I, for example, is obtained by
Procedure a) corresponds to the nucleophilic substitution of a leaving group in a reactive bicyclic system of the formula II by a sulfonamide or one of its salts of the formula III. Because of the higher nucleophilicity and higher reactivity of a sulfonamide present in the salt form, when using a free sulfonamide (formula III, M=H), it is preferred to first generate a sulfonamide salt (formula III, M=metal cation) from this by action of a base. If a free sulfonamide (formula III, M=H) is employed, the deprotonation of the sulfonamide to the salt can be carried out in situ. Preferably, those bases are used which are not alkylated or only slightly alkylated themselves, such as, for example, sodium carbonate, potassium carbonate, sterically strongly hindered amines, e.g., dicyclohexylamine, N,N-dicyclohexylethylamine, or other strong nitrogen bases having low nucleophilicity, for example DBU (diazabicycloundecene), N,N',N'"-triisopropylguanidine etc. However, other customarily used bases can also be employed for the reaction, such as potassium tert-butoxide, sodium methoxide, alkali metal hydrogencarbonates, alkali metal hydroxides, such as, for example, LiOH, NaOH or KOH, or alkaline earth metal hydroxides, such as, for example, Ca(OH).sub.2.
The reaction is preferably carried out in a solvent, particularly preferably in polar organic solvents such as, for example, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), tetramethylurea, (TMU), hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), dimethoxyethane (DME) or other ethers, or, for example, also in a hydrocarbon such as toluene or in a halogenated hydrocarbon such as chloroform or methylene chloride etc. It is also possible to carry out the reaction, however, in polar protic solvents, such as, for example, in water, methanol, ethanol, isopropanol, ethylene glycol or its oligomers and their corresponding hemiethers or alternatively their ethers. The reaction can also be carried out in mixtures of these solvents. It is likewise also possible to carry out the reaction, however, without solvent. The reaction is preferably carried out in a temperature range from -10.degree. C. to +140.degree. C., particularly preferably in a range from 20.degree. C. to 100.degree. C. Conveniently, procedure a) can also be carried out under the conditions of a phase-transfer catalysis.
The compounds of the formula II are obtained according to methods known from the literature, for example from the corresponding alcohols (formula II, L=--OH) by action of hydrogen halide HL (L=Cl, Br, I) or by action of an inorganic acid halide (POCl.sub.3, PCl.sub.3, PCl.sub.5, SOCl.sub.2, SOBr.sub.2) or by free-radical halogenation of the corresponding chroman derivatives (formula II, L=H) with elemental chlorine or bromine, or with free-radical-activatable halogenating agents such as N-bromosuccinimide (NBS) or SO.sub.2 Cl.sub.2 (sulfuryl chloride) in the presence of a radical chain initiator such as energy-rich light of the visible or ultraviolet wavelength range or by use of a chemical free-radical initiator such as azodiisobutyronitrile.
Procedure b)
describes the reaction, which is known per se and frequently used, of a reactive sulfonyl compound of the formula V, in particular of a chlorosulfonyl compound (W=Cl), with an amino derivative of the formula IV to give the corresponding sulfonamide derivative of the formula I. In principle, the reaction can be carried out without solvent, but reactions of this type are in most cases carried out using a solvent.
The reaction is preferably conducted using a polar solvent, preferably in the presence of a base, which can itself be advantageously used as a solvent, e.g., when using triethylamine, in particular pyridine and its homologs. Solvents likewise used are, for example, water, aliphatic alcohols, e.g., methanol, ethanol, isopropanol, sec-butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, and also TMU and HMPA. The reaction is in this case carried out at a temperature from 0.degree. C. to 160.degree. C., preferably from 20.degree. C. to 100.degree. C.
The amines of the formula IV are obtained in a manner known from the literature, preferably from the corresponding carbonyl compounds of the formula XVI ##STR18## in which R(1), R(2), R(5), R(6), R(7), R(8), and R(9) have the meanings indicated above and A is oxygen, either with ammonia or an amine of the formula XVII, EQU R(4)--NH.sub.2 XVII
The compounds of the formula IV in which R(4) is hydrogen can advantageously also be obtained in a manner known from the literature by reduction of oximes or oxime ethers (formula XVI, A is .dbd.N--OR, R=H or alkyl) or hydrazones (formula XVI, A is .dbd.N--NR.sub.2, R is, for example, .dbd.H or alkyl), e.g., using a complex metal hydride or by catalytic hydrogenation. The oximes and hydrazones necessary for this are preferably prepared in a manner known per se from the ketones of the formula XVI (A=oxygen) using hyrdazine or one of its derivatives or, for example, using hydroxylamine hydrochloride under dehydrating conditions. Particularly advantageously, the compounds of the formula IV in which R(4) is hydrogen can also be obtained by amination using a suitable ammonium compound, e.g., ammonium acetate, in the presence of a suitable reductant, such as, for example, NaCNBH.sub.3, (J. Am. Chem. Soc. 93, 1971, 2897).
Alternatively, the amino derivatives of the formula IV can also be obtained in a manner known per se from the literature by reaction of the reactive compounds of the formula II where R(1), R(2), R(5), R(6), R(7), R(8), R(9), and L have the meaning indicated, either with ammonia or an amine of the formula XVII where R(4) has the meaning indicated.
Procedure c)
represents the alkylation reaction, which is known per se, of a sulfonamide or of one of its salts VI with an alkylating agent of the formula VII. Corresponding to the analogy of the reaction to procedure a), the reaction conditions already described in detail under procedure a) apply to procedure c). In addition to the bases already mentioned there, sodium hydride or a phosphazene base are preferably used for the deprotonation of the sulfonamide.
The preparation of the sulfonamide derivatives VI (where M=H) and their precursors has already been described in procedure b), where R(4) is then in each case hydrogen. The preparation of the alkylating agent VII is carried out by analogous literature procedures or as described under procedure a), preferably from the corresponding hydroxy compounds (formula VII where L is --OH).
Procedure d)
describes the further chemical conversion of compounds of the formula I according to the invention into other compounds of the formula I by electrophilic substitution reactions in one or more of the positions designated by R(5) to R(8), which in each case are hydrogen.
Preferred substitution reactions are
Procedure e)
describes the esterification of carboxylic acids of the formula VIII with alcohols of the formula X or XI or amidation with amines of the formula IX. Numerous methods have been described in the literature for these reactions. These reactions can be carried out particularly advantageously by activation of the carboxylic acid, e.g., using dicyclohexylcarbodiimide (DCC), if appropriate with addition of hydroxybenzotriazole (HOBT) or dimethylaminopyridine (DMAP), or using O-(cyano(ethoxycarbonyl)-methylen)amino!-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU). However, reactive acid derivatives can also be synthesized first according to known methods, e.g., acid chlorides by reaction of the carboxylic acids of the formula VIII with inorganic acid halides, such as, for example, SOCl.sub.2, or acid imidazolides by reaction with carbonyldiimidazole, which are then subsequently reacted, if appropriate with addition of an auxiliary base, with the alcohols or amines of the formula IX, X or XI.
The carboxylic acids of the formula VIII are obtained according to the methods described under a) to d), where, however, R(4) is then in each case --C.sub.q H.sub.2q COOH or --C.sub.q H.sub.2q COOalkyl and in the latter case a subsequent hydrolysis of the ester is additionally carried out.
Procedure f)
describes the alkylation of an alcohol of the formula XII using an alkylating agent of the formula XIII or XIV. For this purpose, the alcohol is first converted by action of a suitable base, such as, for example, sodium hydride or a phosphazene base, into an alcoholate salt which is then reacted with the alkylating agent in a suitable polar solvent, such as, for example, dimethylformamide, at temperatures between 20.degree. C. and 150.degree. C. The deprotonation of the alcohol to the salt can also be carried out in situ, bases then preferably being employed which are not alkylated themselves, such as, for example, potassium carbonate.
The alcohols of the formula XII are obtained according to the methods described under a) to d), where then, however, R(4) is in each case --C.sub.q H.sub.2q OH or --C.sub.q H.sub.2q OR (R=suitable protective group, e.g. acetoxy) and in the latter case a subsequent removal of the protective group is additionally carried out.
Procedure g)
corresponds to the nucleophilic opening of an epoxide of the formula XV by a sulfonamide or one of its salts of the formula III. The reaction can be carried out under conditions analogous to those described for procedure a). The use of the free sulfonamide in the presence of a substoichiometric amount, e.g., 20-80%, of the corresponding base, e.g. sodium hydride, has proven particularly advantageous. Likewise advantageous is the use of sulfonamide derivatives in which M is a trialkylsilyl radical, e.g. a trimethylsilyl radical, it then being expedient to carry out the reaction in the presence of a fluoride, e.g., tetrabutylammonium fluoride.
The epoxides of the formula XV are obtained according to methods known from the literature from the corresponding olefins of the formula XVIII ##STR19## in which R(1), R(2), R(5), R(6), R(7), and R(8) have the meanings indicated above, e.g., by action of a suitable inorganic or organic peroxide, such as, for example, H.sub.2 O.sub.2 or m-chloroperbenzoic acid, or by base-catalyzed cyclization of the corresponding bromohydrin, which can be obtained from XVIII, for example, by reaction with N-bromosuccinimide and water. The epoxides of the formula XV can also be obtained from the olefins of the formula XVIII in optically pure form by oxidation in the presence of the chiral Jacobsen catalyst, such as is described, for example, in Tetrahedron Lett. 32, 1991, 5055. The olefins of the formula XVIII can be obtained either from the ketones of the formula XVI (A=oxygen) by reduction of the carbonyl group to an OH function and subsequent acid-catalyzed elimination or by thermal cyclization of suitably substituted aryl propargyl ethers, such as described, for example, in J. Org. Chem. 38 (1973) 3832.
Procedure h)
describes the conversion of a chromanol of the formula Ia into a chromene of the formula Ib by elimination. For this purpose, the chromanol can be subjected to dehydration either directly in the presence of an acid or base or an activation of the hydroxyl group can first be carried out, e.g., by acetylation with acetic anhydride or mesylation with methanesulfonyl chloride, after which a base-catalyzed elimination can subsequently be carried out, e.g. by heating with DBU (diazabicycloundecene).
Apart from the procedures described, a number of other approaches to the compounds of the formula I according to the invention are conceivable. Thus it can be useful, for example, in isolated cases to combine the reactions described under procedures a) to h) with one another in another sequence or, analogously to the methods described, first to prepare compounds not according to the invention in which the radicals R(1) to R(8) have a meaning other than that indicated, and which are then converted into a compound according to the invention in the last stage by a simple conversion of one of the substituents, such as, for example, alkylation, amidation, etc.
In the case of all procedures, it may be appropriate to temporarily protect functional groups in the molecule in certain reaction steps. Such protective group techniques are familiar to the person skilled in the art. The selection of a protective group for groups under consideration and the processes for their introduction and removal are described in the literature and can be adapted to the individual case, if appropriate, without difficulties.
It has already been said that the compounds of the formula I surprisingly have a strong and specific blocking (closing action) on a K.sup.+ channel which is opened by cyclic adenosine monophosphate (cAMP) and fundamentally differs from the well-known K.sup.+ (ATP) channel, and that this K.sup.+ (cAMP) channel identified in colonic tissue is very similar, perhaps even identical, to the I.sub.Ks channel identified in the cardiac muscle. For the compounds according to the invention, it was possible to show a strong blocking action on the I.sub.Ks channel in guinea-pig cardiomyocytes and on the I.sub.sK channel expressed in Xenopus oocytes. As a result of this blocking of the K.sup.+ (cAMP) channel or the I.sub.Ks channel, the compounds according to the invention display pharmacological actions of high therapeutic utility in the living organism and are outstandingly suitable as pharmaceutical active compounds for the therapy and prophylaxis of various syndromes.
Thus the compounds of the formula I according to the invention are distinguished as a novel active compound class of potent inhibitors of stimulated gastric acid secretion. The compounds of the formula I are thus valuable pharmaceutical active compounds for the therapy and prophylaxis of ulcers of the stomach and of the intestinal region, for example of the duodenum. They are likewise suitable on account of their strong gastric secretion-inhibiting action as excellent therapeutics for the therapy and prophylaxis of reflux esophagitis.
The compounds of the formula I according to the invention are furthermore distinguished by an antidiarrheal action and are therefore suitable as pharmaceutical active compounds for the therapy and prophylaxis of diarrheal disorders.
The compounds of the formula I according to the invention are furthermore suitable as pharmaceutical active compounds for the therapy and prophylaxis of cardiovascular disorders. In particular, they can be used for the therapy and prophylaxis of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias, especially of cardiac arrhythmias which can be eliminated by action potential prolongations. They can be used especially for the therapy and prophylaxis of atrial fibrillation and atrial flutters and also for the therapy and prophylaxis of reentry arrhythmias and for the prevention of sudden cardiac death as a result of ventricular fibrillation.
Although numerous substances having antiarrhythmic activity are already on the market, there is still no compound which is really satisfactory with respect to activity, range of application and side effects profile, so there is furthermore a need for the development of improved antiarrhythmics. The action of numerous known antiarrhythmics of the so-called class III is based on an increase in the myocardial refractory time due to prolongation of the action potential duration. This is essentially determined by the extent of repolarizing K.sup.+ currents which flow out of the cell via various K.sup.+ channels. Particularly great importance is ascribed here to the so-called "delayed rectifier" I.sub.K, of which two subtypes exist, a rapidly activated I.sub.Kr and a slowly activated I.sub.Ks. Most known class III antiarrhythmics mainly or exclusively block I.sub.Kr (e.g. dofetilide, d-sotalol). However, it has been shown that these compounds have an increased proarrhythmic risk at low or normal heart rates, in particular arrhythmias which are designated as "torsades de pointes" being observed (D. M. Roden; "Current Status of Class III Antiarrhythmic Drug Therapy"; Am. J. Cardiol. 72 (1993), 44B-49B). In the case of higher heart rates or stimulation of the .beta. receptors, however, the action potential-prolonging action of the I.sub.Kr blockers is markedly reduced, which is attributed to the fact that under these conditions the I.sub.Ks contributes more strongly to the repolarization. For these reasons, the substances according to the invention, which act as I.sub.Ks blockers, have significant advantages compared with the known I.sub.Kr blockers. Meanwhile, it has also been described that a correlation exists between I.sub.Ks channel-inhibitory action and the suppression of life-threatening cardiac arrhythmias, such as are induced, for example, by .beta.-adrenergic hyperstimulation (e.g. B. T. J. Colatsky, C. H. Follmer and C. F. Starmer; "Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias"; Circulation 82 (1990), 2235-2242; A. E. Busch, K. Malloy, W. J. Groh, M. D. Varnum, J. P. Adelman and J. Maylie; "The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit I.sub.sK channels in Xenopus oocytes and I.sub.Ks in guinea pig cardiac myocytes"; Biochem. Biophys. Res. Commun. 202 (1994),265-270).
Moreover, the compounds contribute to a marked improvement of cardiac insufficiency, in particular of congestive heart failure, advantageously in combination with contraction-promoting (positively inotropic) active substances, e.g., phosphodiesterase inhibitors.
In spite of the therapeutically useful advantages which can be achieved by blockade of the I.sub.Ks, to date only very few compounds have been described which inhibit this subtype of the "delayed rectifier". The substance azilimide which is in development admittedly has a blocking action on the I.sub.Ks, but mainly blocks the I.sub.Kr (selectivity 1:10). WO-A-95/14470 claims the use of benzodiazepines as selective blockers of the I.sub.Ks. Further I.sub.Ks blockers are described in FEBS Letters 396 (1996), 271-275: "Specific blockade of slowly activating I.sub.sK channels by chromanols . . . " and Pflugers Arch.--Eur. J. Physiol. 429 (1995), 517-530: "A new class of inhibitors of cAMP-mediated Cl.sup.- secretion in rabbit colon, acting by the reduction of cAMP-activated K.sup.+ conductance". The potency of the 3-hydroxychromanols mentioned there, however, is lower than that of the compounds of the formula I according to the invention.
The compounds of the formula I according to the invention and their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in man as pharmaceuticals per se, as mixtures with one another or in the form of pharmaceutical preparations. The present invention also relates to the compounds of the formula I and their physiologically tolerable salts for use as pharmaceuticals, their use in the therapy and prophylaxis of the syndromes mentioned and their use for the production of medicaments therefor and of medicaments having K.sup.+ channel-blocking action. The present invention furthermore relates to pharmaceutical preparations which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or of a physiologically tolerable salt thereof in addition to customary, pharmaceutically innocuous excipients and auxiliaries. The pharmaceutical preparations normally contain 0.1 to 90 percent by weight of the compounds of the formula I and/or their physiologically tolerable salts. The production of the pharmaceutical preparations can be carried out in a manner known per se. To this end, the compounds of the formula I and/or their physiologically tolerable salts are brought, together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutical active compounds, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Pharmaceuticals which contain compounds of the formula I according to the invention and/or their physiologically tolerable salts can be administered orally, parenterally, e.g., intravenously, rectally, by inhalation or topically, the preferred administration being dependent on the individual case, e.g., the particular clinical picture of the disorder to be treated. The person skilled in the art is familiar on the basis of his expert knowledge with the auxiliaries which are suitable for the desired pharmaceutical formulation. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solublizers, agents for achieving a depot effect, buffer substances or colorants.
The compounds of the formula I can also be combined with other pharmaceutical active compounds to achieve an advantageous therapeutic action. Thus in the treatment of cardiovascular disorders, advantageous combinations with substances having cardiovascular activity are possible. Possible advantageous combination components of this type which are advantageous for cardiovascular disorders are, for example, other antiarrhythmics, i.e., class I, class II or class III antiarrhythmics, such as, for example, I.sub.Kr channel blockers, e.g., dofetilide, or furthermore hypotensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K.sup.+ channel activators, and also alpha- and beta-receptor blockers, but also sympathomimetic compounds and compounds having adrenergic activity, as well as Na.sup.+ /H.sup.+ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances having positively inotropic activity, such as, for example, digitalis glycosides, or diuretics. Combinations with substances having antibiotic activity and with antiulcer agents are furthermore advantageous, for example with H.sub.2 antagonists (e.g., ranitidine, cimetidine, famotidine, etc.), in particular when administered for the treatment of gastrointestinal disorders.
For an oral administration form, the active compounds are mixed with the additives suitable therefor, such as excipients, stabilizers or inert diluents, and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, sugar or starch, in particular maize starch. The preparation can take place here both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Further auxiliaries, also for other administration forms, are, for example, polyethylene glycols and polypropylene glycols.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries. The compounds of the formula I and their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g., ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and also a propellant. Such a preparation customarily contains the active compound in a concentration of approximately 0.1 to 10, in particular of approximately 0.3 to 3, % by weight.
The dose of the active compound of the formula I or of the physiologically tolerable salts thereof to be administered depends on the individual case and is to be adapted to the conditions of the individual case for an optimal action as customary. But it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds in each case employed for therapy or prophylaxis, but also on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the human or animal to be treated and on whether the therapy is acute or prophylactic. Customarily, the daily dose of the compound of the formula I in the case of administration to the patient weighing approximately 75 kg is 0.001 mg/kg of body weight to 100 mg/kg of body weight, preferably 0.01 mg/kg of body weight to 20 mg/kg of body weight. The dose can be administered in the form of an individual dose or divided into a number, e.g., two, three or four, individual doses. In particular when treating acute cases of cardiac arrhythmias, for example in an intensive care unit, a parenteral administration by injection or infusion, e.g., by an intravenous continuous infusion, may be advantageous.
Experimental section