Note: Descriptions are shown in the official language in which they were submitted.
CA 02230349 1998-02-24
HoechstAktiengesellschaft HOE 97/F 038 Dr. v. F.
Description
5 Sulfonamide-substituted fused 7-membered ring compounds, their use as
a medicament, and pharmaceutical preparations comprising them
The present invention relates to compounds of the formula 1,
~ R(3)
S=O
) ~ N R(5)
"Y4~X\4
Y2~ ~ /X3
Y1 X1-X2
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the
meanings indicated in the following, their preparation and their use, in
20 particular in pharmaceuticals. The compounds affect the potassium
channel opened by cyclic adenosine monophosphate (cAMP) or the IKs
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
25 gastrointestinal region or for the treatment of diarrheal disorders.
In pharmaceutical chemistry, in recent years the 4-acylaminochroman
derivatives class and their homologs and analogs have been worked on
intensively. The most prominent representative of this class is cromakalim
30 of the formula A, an example of a homolog is the compound of the formula
B (J. Chem. Soc., Perkin Trans. 1, 1991, 2763).
CA 02230349 1998-02-24
O N
OHH33 \~OH
A B
Cromakalim and other related 4-acylaminochroman derivatives are
10 compounds having a relaxant action on smooth-muscular organs, such
that 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
the 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
15 smooth muscle cells and lead there to opening of specific ATP-sensitive
K+ channels. The increase in negative charge in the cell
(hyperpolarization) induced by the efflux of K+ ions counteracts, via
secondary mechanisms, the increase in the intracellular Ca2+
concentration and thus cell activation, which leads, for example, to muscle
20 contraction.
The compounds of the formula I according to the invention differ
structurally from these acylamino derivatives, in particular by the
replacement of the acylamino group by a sulfonylamino function. While
25 cromakalim (formula A) and the homologs of the formula B and analogous
acylamino compounds act as openers of ATP-sensitive K+ 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+(ATP) channel, but surprisingly show a strong and specific blocking
30 (closing) action on a K+ channel which is opened by cyclic adenosine
monophosphate (cAMP) and differs fundamentally from the K+(ATP)
channel mentioned. More recent investigations show that this K+(cAMP)
CA 02230349 1998-02-24
channel identified in colonic tissue is very similar, perhaps even identical,
to the IKs channel identified in the cardiac muscle. In fact, it was possible
for the compounds of the formula I according to the invention to show a
strong blocking action on the IKs channel in guinea-pig cardiomyocytes
and on the IKs channel expressed in Xenopus oocytes. As a result of this
blockage of the K+(cAMP) channel or of the IKs channel, the compounds
according to the invention display pharmacological actions of high
therapeutic utility in the living body.
Beside the abovementioned cromakalim or acylaminochroman derivatives,
compounds having 4-sulfonylaminochroman structure are also described in
the literature which, however, differ markedly in structure or in biological
action from the compounds of the formula I according to the invention.
Thus EP-A-315 009 describes chroman derivatives having 4-
phenylsulfonylamino structure, which are distinguished by antithrombotic
and antiallergic properties. EP-A-389 861 and EP-A-370 901 describe
3-hydroxychroman derivatives having a 4-sulfonylamino group, which are
described as K+(ATP) channel activators or 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".
The present invention relates to compounds of the formula I
/
S=O
) ~ N R(5)
~,Y4 ~X4
IY3 ~ X3
Y2 J~ /
Y1 X1 - X2
CA 02230349 1998-02-24
in which:
X1 is -O-, -S-, -SO-, -SO2-, -CR(1 )R(2)-, -NR(6)-, -CO- or -CR(1 )R(7)-;
R(1) and R(2)
independently of one another are hydrogen, CF3, C2F5,
C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl,
which is unsubstituted or is substituted by 1 or 2
substitutents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
or
R(1) and R(2)
together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or
10 carbon atoms;
R(6) is hydrogen or -CnH2n-R(8),
where a CH2 group of the group CnH2n can be
replaced by-O-, -CH=CH-, -C-C-, -CO-, -CO-O-,
-O-CO-, -S-, -SO-, -SO2-, -NR(9)- or-CONR(9)-;
R(9) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
n is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
R(8) is hydrogen, CF3, C2F5, C3F7, 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,
where pyridyl, thienyl, imidazolyl and phenyl are
unsubstituted or are substituted by 1 or 2
substituents, selected from the group consisting
of F, Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl,
ethyl, methoxy, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino;
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X2 is -CR(1)R(2)- or -CR(2)R(10)-;
or
X2 if X3 and X1 are -CR(1)R(2)-, are also -O-, -S-, -SO-, -S02- or
-NR(6)-,
where the radicals R(1), R(2) and R(6)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
R(10) together with R(7) is a bond;
X3 is -CR(1 )R(2)-;
or
X3 if X2 and X4 are -CR(1)R(2)-, are also -O-, -S-, -SO-, -S02- or
-NR(6)-,
where the radicals R(1), R(2) and R(6)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
X4 is -CR(1 )R(2)-, -NR(6)-, -NR(11 )-, -CH(OR(30))- or -CR(2)R(11 )-,
where the radicals R(1), R(2) and R(6)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl
having 1, 2, 3 or 4 carbon atoms;
R(11) togetherwith R(5) is a bond;
Y1, Y2, Y3 and Y4
independently of one another are -CR(12)- or N,
where at most 2 of the groups Y1, Y2, Y3 and Y4 can
simultaneously be N;
the radicals R(12)
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, CF3, C2F5, C3F7, N3, NO2,
-Z-CmH2m-R(13) or phenyl,
which is unsubstituted or is substituted by 1 or 2
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substituents selected from the group consisting of F,
Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
Z is-O-,-CO-,-CO-O-,-O-CO-,-S-,-SO-,-S02-,
-S02NR(14)-, -NR(14)- or-CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m iszero, 1, 2, 3,4, 50r6;
R(13) is hydrogen, CF3, C2F5, C3F7, cycloalkyl having 3, 4,
5, 6, 7 or 8 carbon atoms, -NR(15)R(16),
-CONR(15)R(16), -OR(30a), phenyl, thienyl or an
N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or
9 carbon atoms,
where phenyl, thienyl and the N-containing
heterocycle are unsubstituted or are substituted
by 1 or 2 substituents selected from the group
consisting of F, Cl, Br, I, CF3, N02, CN, NH2,
OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and
methylsulfonylamino;
R(15) and R(16)
independently of one another are 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 a CH2 group can be replaced
by -O-, -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;
CA 02230349 1998-02-24
or
Y1 and Y2
together are a sulfur atom and Y3 and Y4 in each case are
-CR(1 2)-;
the radicals R(12)
independently of one another are as defined for Y1, Y2, Y3,
Y4;
R(3) is R(17)-CxH2x-NR(18) or R(17)-CXH2x-,
where a CH2 group in the groups CXH2x can be replaced by
-O-, -CO-, -S-, -SO-, -SO2- or-NR(19)-;
R(19) is hydrogen, methyl or ethyl;
R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, CF3, C2F5 or C3F7;
x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
or
R(18) and R(17)
together are a bond if x is not smaller than 3;
or
R(3) is phenyl,
which is unsubstituted or is substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, Br, I, CF3, NO2,
CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R(3) together with R(4)
is an alkylene chain having 3, 4, 5, 6, 7, or 8 carbon atoms,
where a CH2 group of the alkylene chain can be replaced by
-O-, -CO-, -S-, -SO- or SO2-;
R(4) iS-crH2r-R(2o)l
where a CH2 group of the group CrH2r can be replaced by
CA 02230349 1998-02-24
-O-, -CH=CH-, -C - C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-,
-SO2-, -NR(21)- or -CONR(21)-;
R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17,
1 8, 1 9 or 20;
R(20) is hydrogen, methyl, CF3, C2F5, C3F7, cycloalkyl having 3,
4, 5, 6, 7 or 8 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,
where phenyl, thienyl and the N-containing heterocycle
are unsubstituted or are substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
1 5 and methylsulfonylamino;
R(22) and R(23)
independently of one another are hydrogen or alkyl
having 1, 2 or 3 carbon atoms;
or
N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9
carbon atoms,
where phenyl, thienyl and the N-containing
hererocycle are unsubstituted or are substituted by 1
or2
substituents selected from the group consisting of F,
Cl, Br, I, CF3 NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
R(22) and R(23)
independently of one another are hydrogen or alkyl
having 1, 2 or 3 carbon atoms;
R(22) and R(23)
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together are a chain of 4 or 5 methylene groups, of
which a CH2 group can be replaced by-O-, -S-, -NH-,
-N(CH3)- or-N(benzyl)-;
R(5) is hydrogen ortogetherwith R(11) is a bond;
in all their stereoisomeric forms and mixtures thereof in any desired ratios,
and also their physiologically tolerable salts.
Preferred compounds of the formula I are those in which X1, X2, X3, X4,
Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the meanings indicated above,
but where one of the radicals R(3) and R(4), in particular the radical R(3),
has a meaning other than hydrogen, and moreover compounds of the
formula I in which both radicals R(3) and R(4) have meanings other than
hydrogen, in all their stereoisomeric forms and mixtures thereof in any
desired ratios, and also their physiologically tolerable salts.
1 5
Particularly preferred compounds of the formula I are those in which:
X1 is -O-, -S-, -SO-, -SO2-, -CR(1)R(2)- or-NR(6)-;
R(1) and R(2)
independently of one another are hydrogen, CF3, C2F5,
C3F7, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl,
which is unsubstituted or is substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
or
R(1) and R(2)
together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or
10 carbon atoms;
R(6) is hydrogen or -CnH2n-R(8),
where a CH2 group of the group CnH2n can be
replaced by-O-, -CH=CH-, -C-C-, -CO-,-CO-O-,
CA 02230349 1998-02-24
-O-CO-, -S-, -SO-, -SO2-, -NR(9)- or-CONR(9)-;
R(9) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
n is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
R(8) is hydrogen, CF3, C2F5, C3F7, 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,
where pyridyl, thienyl, imidazolyl and phenyl are
unsubstituted or are substituted by 1 or 2
substituents selected from the group consisting
of F, Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl,
ethyl, methoxy, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino;
X2 is-CR(1)R(2)-;
where the radicals R(1 ) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
X3 is-CR(1)R(2)-,
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
X4 is -CR(1)R(2)-, -NR(6)-, -NR(11)- or-CH(OR(30))-;
where the radicals R(1), R(2~ and R(6)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl
having 1, 2, 3 or 4 carbon atoms;
R(11) togetherwith R(5), is a bond;
Y1, Y2, Y3 and Y4
independently of one another are -CR(12)- or N,
CA 02230349 1998-02-24
where at most 2 of the groups Y1, Y2, Y3 and Y4 can
simultaneously be N;
the radicals R(12)
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
or 6 carbon atoms, CN, CF3, C2F5, C3F7, N3, N02,
-Z-CmH2m-R(13) or phenyl,
which is unsubstituted or is substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
Z is-O-,-CO-,-CO-O-,-O-CO-,-S-,-SO-,-S02-,
-S02NR(14)-, -NR(14)- or-CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m iszero, 1,2, 3,4, 50r6;
R(13) is hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 carbon
atoms, -NR(1 5)R(16), -CONR(1 5)R(16), -OR(30a),
phenyl, thienyl or an N-containing heterocycle having
1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, thienyl and the N-containing
heterocycle are unsubstituted or are substituted
by 1 or 2 substituents selected from the group
consisting of F, Cl, Br, I, CF3, N02, CN, NH2,
OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and
methylsulfonylamino;
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1, 2 or 3 carbon atoms;
or
CA 02230349 1998-02-24
R(15) and R(16)
together are a chain of 4 or 5 methylene
groups, of which a CH2 group can be replaced
by -O-, -S-, -NH-, -N(CH3)- or-N(benzyl)-;
R(30a)
is hydrogen, alkyl having 1, 2 or 3 carbon atoms
or acyl having 1, 2, 3 or 4 carbon atoms;
or
Y1 and Y2
together are a sulfur atom and Y3 and Y4 in each case are
-CR(12)-;
the radicals R(12)
independently of one another are defined as for Y1, Y2, Y3,
Y4;
1 5 R(3) is R(17)-CxH2x-NR(18)- or R(17)-CXH2x-,
where a CH2 group in the groups CXH2x can be replaced by
-O-, -CO-, -S-, -SO-, -S02- or -NR(19)-;
R(19) is hydrogen, methyl or ethyl;
R(17) is hydrogen, methyl, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, CF3, C2F5 or C3F7;
x iszero,1,2,3,4,5,6,7,8,90r10;
R(18) is hydrogen or alkyl having 1, 2, 3,4, 5, 6,7 or 8 carbon
atoms;
or
R(18) and R(17)
together are a bond if x is not smaller than 3;
or
R(3) is phenyl,
which is unsubstituted or is substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, Br, l, CF3, N02,
CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and methylsulfonylamino;
CA 02230349 1998-02-24
or
R(3) together with R(4)
is an alkylene chain having 3, 4, 5, 6, 7, or 8 carbon atoms,
where a CH2 group of the alkylene chain can be replaced by
-O-, -CO-, -S-, -SO- or SO2-;
R(4) iS-crH2r-R(2o)~
where a CH2 group of the group CrH2r can be replaced by
-O-, -CH=CH-, -C - C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-,
-SO2-, -NR(21)- or-CONR(21)-;
R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
r is zero, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 1 1 , 1 2, 1 3, 14, 1 5, 1 6, 1 7,
1 8, 1 9 or 20;
R(20) is hydrogen, methyl, CF3, C2F5, 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,
where phenyl, thienyl and the N-containing heterocycle
are unsubstituted or are substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
R(22) and R(23)
independently of one another are 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,
of which a CH2 group can be replaced by -O-,
-S-, -NH-, -N(CH3)- or-N(benzyl)-;
R(5) is hydrogen ortogetherwith R(11) is a bond;
in all their stereoisomeric forms and mixtures thereof in any desired ratios,
CA 02230349 l998-02-24
14
and also their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
X1 is -O-, -S-, -SO-, -SO2-, -CR~1)R(2)- or-NR(6)-;
R(1 ) and R(2)
independently of one another are hydrogen, CF3, 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 hydrogen or-CnH2n-R(8),
where a CH2 group of the group CnH2n can be
replaced by-O, -CH=CH-, -C-C-, -CO-, -CO-O-,
-O-CO-, -S-, -SO-, -SO2-, -NR(9)- or -CONR(9)-;
R(9) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
n is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
R(8) is hydrogen, CF3, 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,
where pyridyl, thienyl, imidazolyl and phenyl are
unsubstituted or are substituted by 1 or 2
substituents selected from the group consisting
of F, Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl,
ethyl, methoxy, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino;
X2 is -CR(1 )R(2)-,
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
CA 02230349 1998-02-24
X3 is -CR(1)R(2)-,
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
X4 is -CR(1)R(2)-, -NR(6)-, -NR(11)- or-CH(OR(30))-;
where the radicals R(1), R(2) and R(6)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl
1 0 having 1, 2, 3 or 4 carbon atoms;
R(11) together with R(5) is a bond;
Y1, Y2, Y3 and Y4
independently of one another are -CR(12)-;
the radicals R(12)
1 5 independently of one another are hydrogen, F, Cl, Br, l, alkyl
having 1, 2, 3, 4 or 5 Garbon atoms, cycloalkyl having 3, 4, 5
or 6 carbon atoms, CN, CF3, C2Fs, C3F7, N3, NO2,
-Z-CmH2m-R(13) or phenyl,
which is unsubstituted or is substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, l, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
Z is-O-,-CO-, -CO-O-,-O-CO-, -S-,-SO-, -SO2-,
-SO2NR(14)-, -NR(14)- or -CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m is zero, 1, 2, 3, 4, 5 or 6;
R(13) is hydrogen, CF3, cycloalkyl having 3, 4, 5 or 6 carbon
atoms, -NR(15)R(16), -CONR(15)R(16), -OR(30a),
phenyl, thienyl or an N-containing heterocycle having
1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
CA 02230349 1998-02-24
16
where phenyl, thienyl and the N-containing
heterocycle are unsubstituted or are substituted
by 1 or 2 substituents selected from the group
consisting of F, Cl, Br, I, CF3, N02, CN, NH2,
OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and
methylsulfonylamino;
R(15) and R(16)
independently of one another are hydrogen or
alkyl havïng 1, 2 or 3 carbon atoms;
or
R(15) and R(16)
together are a chain of 4 or 5 methylene groups
of which a CH2 group can be replaced by -O-,
-S-, -NH-, -N(CH3)- or-N(benzyl)-;
R(30a)
is hydrogen, alkyl having 1, 2 or 3 carbon atoms
or acyl having 1, 2, 3 or 4 carbon atoms;
or
20 Y1 and Y2
together are a sulfur atom and Y3 and Y4 are each -CR(12)-;
the radicals R(12)
independently of one another are as defined for Y1, Y2, Y3,
Y4;
R(3) is R(17)-CXH2x-NR(18~- or R(17)-CXH2x-,
where a CH2 group in the groups CXH2x can be replaced by
-O-, -CO-, -S-, -SO-, -SO2- or-NR(19)-;
R(19) is hydrogen, methyl or ethyl;
R(17) is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3,
C2F5 or C3F7;
x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R(18) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
CA 02230349 1998-02-24
atoms;
or
R(18) and R(17)
together are a bond, if x is not smaller than 3;
5 or
R(3) is phenyl,
which is unsubstituted or is substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, Br, I, CF3, NO2,
CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4) is-CrH2r-R(20),
where a CH2 group of the group CrH2r can be replaced by
-O-, -CH=CH-, -C - C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-,
-S02-, -NR(21)- or-CONR(21)-;
R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R(20) is methyl, CF3, C2F5, 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,
where phenyl, thienyl and the N-containing heterocycle
are unsubstituted or are substituted by 1 or 2
substituents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
R(22) and R(23)
independently of one another are 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, of
CA 02230349 1998-02-24
which a CH2 group can be replaced by -O-, -S-, -NH-,
-N(CH3)- or-N(benzyl)-;
R(5) is hydrogen or together with R(11) is a bond;
in all their stereoisomeric forms and mixtures thereof in any desired ratios,
5 and also their physiologically tolerable salts.
Especially preferred compounds of the formula I are those in which:
X1 is -O- or-CR(1)R(2)-;
R(1) and R(2)
independently of one another are hydrogen, CF3, alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms;
X2 is -CR(1 )R(2)-,
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
1 5 meanings of the radicals in X1;
X3 is -CR(1 )R(2)-,
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
X4 is -CR(1)R(2)- or -CH(OR(30))-;
where the radicals R(1) and R(2)
are defined as indicated for X1, but are independent of the
meanings of the radicals in X1;
R(30) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl
having 1, 2, 3 or 4 carbon atoms;
Y1, Y2, Y3 and Y4
independently of one another are -CR(12)-;
the radicals R(12)
independently of one another are hydrogen, F, Cl, Br, I, alkyl
having 1, 2, 3, 4 or 5 carbon atoms, CN, CF3, NO2,
-Z-CmH2m-R(13) or phenyl,
which is unsubstituted or is substituted by 1 or 2
CA 02230349 1998-02-24
1 9
substituents selected from the group consisting of F,
Cl, Br, I, CF3, NO2, CN, NH2, OH, methyl, ethyl,
methoxy, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino;
Z is-O-,-CO-,-CO-O-,-O-CO-,-S-, -SO-,-SO2-,
-SO2NR(14)-, -NR(14)- or -CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m is zero, 1, 2 or 3;
R(13) is hydrogen, CF3, -NR(1 5)R(16), -CONR(1 5)R(16),
-OR(30a), phenyl, thienyl or an N-containing
heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon
atoms,
where phenyl, thienyl or the N-containing
heterocycle are unsubstituted or are substituted
by 1 or 2 substituents selected from the group
consisting of F, Cl, Br, I, CF3, NO2, CN, NH2,
OH, methyl, ethyl, methoxy, dimethylamino,
sulfamoyl, methylsulfonyl and
methylsulfonylamino;
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1, 2 or 3 carbon atoms;
or
2 5 R(15) and R(16)
together are a chain of 4 or 5 methylene
groups, of which a CH2 group can be replaced
by -O-, -S-, -NH-, -N(CH3)- or -N(benzyl)-;
R(30a)
is hydrogen, alkyl having 1, 2 or 3 carbon atoms
or acyl having 1, 2, 3 or 4 carbon atoms;
R(3) is R( 1 7)-CxH2x-~
CA 02230349 1998-02-24
R(17) is methyl, cycloalkyl having 3, 4, 5 or 6 carbon atoms or CF3;
x is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R(4) iS-crH2r-R(2o)~
where a CH2 group of the group CrH2r can 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 zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R(20) is methyl, CF3 or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
R(5) is hydrogen;
10 in all their stereoisomeric forms and mixtures thereof in any desired ratios, and also their physiologically tolerable salts.
Particularly especially preferred compounds of the formula I are those in
which:
15 X1 is -O- or -CH2;
X2 is -CR(1 )R(2)-,
R(1) and R(2)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
20 X3 is-CH2-or-C(CH3)2-;
X4 is -CH2- or -CHOH-;
Y1, Y2, Y3 and Y4
independently of one another are -CR(12)-;
the radicals R(12)
independently of one another are hydrogen, F, Cl, Br, alkyl
having 1, 2 or 3 carbon atoms, CN, CF3, NO2,
-Z-CmH2m-R(1 3);
Z is-O-, -CO-,-CO-O-, -O-CO-, -S-, -SO-, -S02-,
-SO2NR(14)-, -NR(14)- or-CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m is zero, 1, 2 or 3;
CA 02230349 1998-02-24
R(13) is hydrogen, CF3, -NR(15)R(16), phenyl, piperidyl,
1-pyrrolidinyl, 4-morpholinyl, 4-methylpiperazin-1-yl, pyridyl,
thienyl or imidazolyl;
R(15) and R(16~
independently of one another are hydrogen or
alkyl having 1, 2 or 3 carbon atoms;
R(3) is R(1 7)-CxH2x-~
R(17) is methyl;
x is zero, 1, 2 or 3;
R(4) iS-crH2r-R(2o)~
where a CH2 group of the group CrH2r can 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 iszero, 1,2, 3,4, 50r6;
1 5 R(20) is methyl, CF3 or pyridyl;
R(5) is hydrogen;
in all their stereoisomeric forms and mixtures thereof in any desired ratios,
and also their physiologically tolerable salts.
Very particularly especially preferred compounds of the formula I are those
in which:
X1 is-O-;
X2 is -CR(1 )R(2)-,
R(1) and R(2)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
X3 is -CH2 or -C(CH3)2-;
X4 is-CH2-;
Y1 is CH;
30 Y2 is CH;
Y4 is CH;
Y3 is-CR(12)-;
CA 02230349 1998-02-24
R(1 2)
is F, Cl, Br, alkyl having 1, 2 or 3 carbon atoms, CN, CF3,
N02, -Z-CmH2m-R(1 3);
Z is-O-,-CO-,-C(~-O-,-O-CO-,-S-,-SO-,-S02-,
-S02NR(14)- or -CONR(14)-;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon
atoms;
m is 1, 20r3;
R(13) is hydrogen, CF3, pyridyl or phenyl;
10 R(3) is R(17)-CXH2x~~
R(17) is methyl;
x iszero, 1 or2;
R(4) is-CrH2r-R(20),
where a CH2 group of the group CrH2r can be replaced by
-O-, -CO-O-, -O-CO- or-CONR(21)-;
R(21) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
r is zero, 1, 2, 3, 4, 5 or6;
R(20) is methyl or CF3;
R(5) is hydrogen;
20 in all their stereoisomeric forms and mixtures thereof in any desired ratios, and also 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 CnH2n, CmH2m,
25 CXH2x and CrH2r. 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,
30 neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl,
nonadecyl, eicosyl. The bivalent radicals derived from these radicals, e.g.
CA 02230349 1998-02-24
23
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. an~ examples of alkylene radicals.
Examples of acyl radicals are formyl, acetyl, propionyl, n-butyryl or
5 isobutyryl.
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.
20 Particularly preferred N-containing heterocycles are pyrrolyl, imidazolyl,
quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
Thienyl is either 2- or 3-thienyl.
25 Monosubstituted phenyl radicals can be substituted in the 2-, the 3- or the
4-position, disubstituted phenyl radicals in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-position. Correspondingly, the same also applies analogously to the N-
containing heterocycles or the thiophene radical.
30 In the case of disubstitution of a radical, the substituents can be identical or
different.
CA 02230349 1998-02-24
24
If the radicals R(1 ) and R(2) together are an alkylene chain, these radicals
with the carbon atom carrying them form a ring which has a carbon atom in
common with the 7-membered ring in the formula l; thus a spiro compound
is then present. If R(7) and R(10) together are a bond, a double bond is
5 present between the groups X1 and X2. Correspondingly, if R(5) and R(11 )
together are a bond, a double bond is present between the group X4 and
the carbon atom which carries the radical R(3)-SO2-NR(4)-. If R(17) and
R(18) together are a bond, the group R(1 7)-CXH2x-NR(18)- is preferably a
nitrogen heterocycle bonded via a nitrogen atom. If R(17) and R(18)
together are a bond and the group R(17)-CXH2x-NR(18)- 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 Y1 and Y2
together are a sulfur atom, the structural unit -Y2=Y1- is thus -S-, thus the
15 7-membered ring in the formula I is in this case fused to a thiophene 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 relates to the
corresponding physiologically or toxicologically tolerable salts, in particular
20 the pharmaceutically utilizable salts. Thus the compounds of the formula I
which carry acidic groups, e.g. one or more COOH groups, can be used,
for example, as alkali metal salts, preferably sodium or potassium salts, or
as alkaline earth metal salts, e.g. calcium or magnesium salts, or as
ammonium salts, e.g. as salts with ammonia or organic amines or amino
25 acids. Compounds of the formula I which contain 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,
30 fumarates, malates, gluconates etc. If the compounds of the formula I
simultaneously contain acidic and basic groups in the molecule, in addition
to the salt forms described, the invention also includes internal salts,
CA 02230349 1998-02-24
so-called betaines. Salts can be obtained from the compounds of the
formula I by customary processes, for example by combination with an acid
or base in a solvent or dispersant or alternatively from other salts by anion
exchange.
When appropriately substituted, 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
10 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 levo- and
dextrorotatory antipodes, and also in the form of mixtures of the two
15 enantiomers in different ratios or in the form of racemates. If cis/trans
isomerism is present, both the cis form and the trans form and mixtures of
these forms are included in the invention. The preparation of individual
stereoisomers can be carried out, if desired, by resolution of a mixture
according to customary methods or, for example, by stereoselective
20 synthesis. If mobile hydrogen atoms are present, the present invention also
includes all tautomeric forms of the compounds of the formula 1.
The compounds of the formula I can be prepared by different chemical
processes. Thus, for example, a compound of the formula I is obtained by
CA 02230349 1998-02-24
26
a) reacting a compound of the formula ll a or of the formula ll b
Y2 ~Y4~
Y1 X1-X2 Y1 X1-X2
lla llb
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4 and R(5) have the meanings
10 indicated above and L is a nucleofugic leaving group, in particular a
customary nucleofugic leaving group such as, for example, F, Cl, Br, I,
methanesulfonyloxy or p-toluenesulfonyloxy, in a manner known per se
with a sulfonamide or its salts of the formula lll
0~ ~
R(4) / R(3) lll
M
in which R(3) and R(4) have the meanings indicated above and M is
20 hydrogen or preferably a metal atom, particularly preferably lithium, sodium
or potassium, or in the case of a reaction with a compound of the formula
Il b, also a trialkylsilyl radical, e.g. a trimethylsilyl radical;
or by
25 b) reacting a compound of the formula IV
( ) ~ N R(5)
"Y4~ X4
1 ~ ~X3 IV
Y1 X1 -- X2
CA 02230349 1998-02-24
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(4) and R(5) have the meanings
indicated above, with a sulfonic acid derivative of the formula V
0~ ~
/S--R(3) V
W
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
c) reacting a compound of the formula Vl
\\ /
15S=0
M
"y4~X\4 Vl
l X3
Y2~, \
Y1 X1-X2
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(5) 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 Vll
2 5 R(4)-L Vl I
in which R(4) has the meanings indicated above with the exception of
hydrogen and L has the meanings indicated above;
30 or by
CA 02230349 1998-02-24
28
d) carrying out, in a compound of the formula I
/
S=O
R(4)--N/
,~Y4 ~X4
Yl 3 ~ \X3
Y2~
Y1 X1 - X2
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the
meanings indicated above, an electrophilic substitution reaction in at least
one of the positions Y1 to Y4, provided a CH group is present in this
position, or carrying out a chemical conversion, e.g. an alkylation or
acylation, in at least one of the positions X1 to X4.
1 5
The procedure a) corresponds to the nucleophilic substitution of a leaving
group in a reactive bicyclic system of the formula ll a or ll b by a
sulfonamide or one of its salts of the formula lll. Because of the higher
nucleophilicity and higher reactivity of a sulfonamide present in the salt
form, when using a free sulfonamide (formula lll, M = H) it is preferred to
generate a sulfonamide salt (formula lll, M = metal cation) from this first by
the action of a base. If a free sulfonamide (formula lll, 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 with low
nucleophilicity, for example DBU (diazabicycloundecene), N,N',N"'-
triisopropylguanidine etc. However, it is also possible to employ other
customarily used bases 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
CA 02230349 1998-02-24
metal hydroxides, such as, for example Ca(OH)2 . In the case of a reaction
of an epoxide of the formula ll b with a trialkyl- or trimethylsilylsulfonamide
of the formula lll, it is advantageous to carry out the reaction in the
presence of a fluoride, e.g. tetrabutylammonium fluoride.
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 (HMPT), tetrahydrofuran (THF),
10 dimethoxyethane (DME) or other ethers, or, for example, alternatively in a
hydrocarbon such as toluene or in a halogenated hydrocarbon such as
chloroform or methylene chloride etc. However, the reaction can also be
carried out in polar protic solvents, such as, for example, in water,
methanol, ethanol, isopropanol, ethylene glycol or its oligomers and their
15 corresponding hemiethers or alternatively their ethers. The reaction can
also be carried out in mixtures of these solvents. The reaction can equally
be carried out, however, entirely without solvent. The reaction is preferably
carried out in a temperature range from -10 to +140~C, particularly
preferably in the range from 20 to 1 00~C. Favorably, procedure a) can also
20 be carried out under the conditions of a phase-transfer catalysis.
The compounds of the formula ll a are obtained by methods known from
the literature, for example from the corresponding alcohols (formula ll a,
L = OH, R(5) = H) by the action of a hydrogen halide of the formula HL
25 (L = Cl, Br, I) or by the action of an inorganic acid halide (e.g. POCI3, PCI3,
PCI5, SOCI2, SOBr2), or, for example, by free-radical halogenation of the
corresponding compounds of the formula ll a where L = H and R(5) = H
with elemental chlorine or bromine or with halogenating agents which can
be activated by free radicals, such as, for example, N-bromosuccinimide
30 (NBS) or sulfuryl chloride (SO2CI2). In the case of free-radical
halogenation, the reaction is in general carried out in the presence of a
radical chain initiator such as energy-rich light of the visible or ultraviolet
CA 02230349 1998-02-24
wave range or using a chemical free-radical initiator such as, for example,
azodiisobutyronitrile.
The compounds of the formula ll a, in which X4 is -NR(11)- and R(5)
5 together with R(11 ) is a bond, are obtained, for example, from the
corresponding lactams (formula ll a, L and R(5) are together a carbonyl
oxygen atom, X4 = NH) by the action of an inorganic acid halide (e.g.
POCI3, PCI3, PCls, SOCI2, SOBr2)
10 The compounds of the formula ll b are obtained by methods known from
the literature, from the corresponding olefins of the formula ll c
"Y4~
l X3 llc
Y2~, \
Y1 X1-X2
in which X1, X2, X3, Y1, Y2, Y3 and Y4 have the meanings indicated
above, e.g. by the action of a suitable inorganic or organic peroxide, such
as, for example, H2O2 or m-chloroperbenzoic acid, or by base-catalyzed
cyclization of the corresponding bromohydrin, which can be obtained from
Il c, for example, by reaction with N-bromosuccinimide and water.
The epoxides of the formula ll b can also be obtained in optically pure form
from the olefins of the formula ll c by oxidation in the presence of the chiral
Jacobsen catalyst, such as, for example, in Tetrahedron Lett. 32, 1991,
5055.
The procedure b) corresponds to the reaction, which is known per se andfrequently 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
30 formula 1. The reaction can also be carried out without solvent, but
reactions of this type are in most cases carried out using a solvent. The
reaction is preferably carried out using a polar solvent, particularly
CA 02230349 1998-02-24
preferably in the presence of a base, which itself can advantageously be
used as a solvent, e.g. using triethylamine or in particular pyridine or its
homologs. Suitable solvents are, for example, water, aliphatic alcohols,
e.g. methanol, ethanol, isopropanol, sec-butanol, ethylene glycol,
5 monoalkyl- and dialkyl ethers of monomeric and oligomeric ethylene glycol,
tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, and also
TMU and HMPT. In this case, the reaction is in general carried out at a
temperature from 0 to 160~C, preferably from 20 to 1 00~C.
10 The amines of the formula IV are obtained in a manner known from the
literature, preferably from the corresponding carbonyl compounds of the
formula Vlll
A
~Y4 ~X4
IY23~ X X3 Vlll
Y1 X1-X2
in which X1, X2, X3, X4, Y1, Y2, Y3 and Y4 have the meanings indicated
above and A is oxygen, either with ammonia or an amine of the formula IX
R(4)-NH2 IX
in which R(4) has the meanings indicated, under reductive conditions or
reductive catalytic conditions, preferably at elevated temperature and in an
25 autoclave. In this case, by condensation reaction of the ketones of the
formula Vlll (A = oxygen) and of the amines of the formula IX in situ, Schiff
bases of the formula Vlll in which a is R(4)-N= are primarily formed, which
can be converted directly, i.e. without prior isolation, under reductive
conditions into the amines of the formula IV. However, the Schiff bases
30 (formula Vlll, A is R(4)-N=) intermediately formed, in the condensation
reaction, from the compounds of the formulae Vlll and IX can be prepared
by methods known from the literature and first isolated in order to then
CA 02230349 1998-02-24
convert them in a separate step with a suitable reducing agent, such as, for
example, NaBH4, LiAlH4, NaBH3CN 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.
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 Vlll, A is =N-OR, R = H or
alkyl) or hydrazones (formula Vlll, A is =N-NR2, R, for example = H or
10 alkyl), e.g. using a complex metal hydride or by catalytic hydrogenation.
The oximes and hydrazones necessary for this purpose are preferably
prepared in a manner known per se from the ketones of the formula Vlll
(A = oxygen) with hydrazine or one of its derivatives or, for example, with
hydroxylamine hydrochloride under dehydrating conditions.
1 5
The procedure c) represents the alkylation reaction known per se of a
sulfonamide or of one of its salts (formula Vl) with an alkylating agent
(formula Vll). Corresponding to the analogy of the reaction to procedure a),
the reaction conditions already described in detail under procedure a)
20 apply to procedure c).
The preparation of the sulfonamide derivatives of the formula Vl and their
precursors has already been described in procedure b). The preparation of
the alkylating agents of the formula Vll is carried out analogously to
25 procedures in the literature or as described under procedure a), preferably
from the corresponding hydroxy compounds (formula Vll, L = hydroxyl).
The procedure d) corresponds to the further chemical conversion of
compounds of the formula I according to the invention into other
30 compounds of the formula I according to the invention, e.g. by electrophilic
substitution reactions in one or in more of the positions marked by Y1 to
Y4, if these are CH. Preferred substitution reactions are
CA 02230349 1998-02-24
1. aromatic nitration for the introduction of one or more nitro groups, which
in subsequent reactions can in some cases or all be reduced to amino
groups. The amino groups can in turn be converted into other groups in
subsequent reactions, for example in a Sandmeyer reaction, e.g. for the
5 introduction of cyano groups;
2. aromatic halogenation, in particular for the introduction of chlorine,
bromine or iodine;
10 3. chlorosulfonation, e.g. by action of chlorosulfonic acid, for the
introduction of a chlorosulfonyl group which can be converted into other
groups in subsequent reactions, e.g. into a sulfonamido group;
4. the Friedel-Crafts acylation reaction for the introduction of an acyl radical15 or of a sulfonyl radical by action of the corresponding acid chlorides in thepresence of a Lewis acid as a Friedel-Crafts catalyst, preferably in the
presence of anhydrous aluminum chloride.
Further chemical conversions of compounds of the formula I according to
20 the invention which are possible are, for example, reactions in the positionsX1 to X4. Thus, for example, compounds of the formula I according to the
invention (X4 = CHOH) can be converted by alkylation or acylation with a
compound of the formula L-R(30), where L has the meanings indicated
above and R(30) has the meanings indicated above with the exception of
25 hydrogen, into the corresponding alkyl or acyl derivatives of the formula I
(X4 = CHOR(30)). Furthermore, the hydroxyl group, for example, can be
eliminated by dehydrating agents, such that a compound of the formula I in
which R(5) and R(11) together form a bond is obtained.
30 In 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 choice of a
CA 02230349 1998-02-24
34
protective group for groups coming into consideration and the processes
for their introduction and removal are described in the literature and can be
adapted to the individual case, if appropriate, withcut difficulties.
5 The bicyclic precursors required for the above processes are either known
from the literature or can be prepared analogously to known processes.
Some methods for the preparation of these precursors are described, for
example, in the following literature references, which in this regard are in
full part of the present disclosure: J. Chem. Soc., Perkin Trans. 1, 1991,
2763; Eur. J. Med. Chem. 30 (1995), 377; Ind. J. Chem. 9 (1971), 809;
J. Heterocyclic Chem. 26 (1989),1547.
It has already been said that the compounds of the formula I surprisingly
have a strong and specific blocking (closing) action on a K+ channel which
1 5 is opened by cyclic adenosine monophosphate (cAMP) and fundamentally
differs from the well-known K+(ATP) channel, and that this K+(cAMP)
channel identified in colonic tissue is very similar, perhaps even identical,
to the IKs channel identified in the cardiac muscle. For the compounds
according to the invention, it was possible to show a strong blocking action
20 on the IKs channel in guinea-pig cardiomyocytes and in the IsK channel
expressed in Xenopus oocytes. As a result of this blocking of the
K+(cAMP) channel or of the IKs channel, the compounds according to the
invention display pharmacological actions of high therapeutic utility in the
living body and are outstandingly suitable as pharmaceutical active
25 compounds for the therapy and prophylaxis of various syndromes.
Thus the compounds of the formula l 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
30 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 also suitable, on account of their strong gastric
CA 02230349 1998-02-24
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
5 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
10 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 prolongation. They
15 can be specifically used for the therapy and prophylaxis of atrial fibrillation
and atrial flutter, and for the therapy and prophylaxis of reentry arrhythmias
and for the prevention of sudden heart death as a result of ventricular
fibrillation.
20 Although numerous substances having antiarrhythmic activity are already
on the market, there is nevertheless no compound which is really
satisfactory with respect to activity, range of application and side-effect
profile, so that there is furthermore a need for the development of improved
antiarrhythmics. The action of numerous known antiarrhythmics of the
25 so-called class lll is based on an increase in the myocardial refractory
period by prolongation of the action potential duration. This is essentially
determined by the extent or repolarizing K+ streams which flow out of the
cell via various K+ channels. Particularly great importance is ascribed to
the so-called "delayed rectifier" IK, of which two subtypes exist, a rapidly
30 activated IKr and a slowly activated IKs. Most known class lll
antiarrhythmics block IKr predominantly or exclusively (e.g. dofetilide,
d-sotalol). It has been shown, however, that these compounds have an
CA 02230349 1998-02-24
36
increased proarrhythmic risk at low or normal heart rates, arrhythmias
which are designated as "torsades de pointes" in particular being observed
(D.M. Roden; "Current Status of Class lll Antiarrhythmic Drug Therapy";
Am. J. Cardiol. 72 (1993), 44B - 49B). In the case of higher heart rates or
stimulation of the 13-receptors, however, the action potential-prolonging
action of the IKr blockers is markedly reduced, which is attributed to the
fact that under these conditions the IK5 contributes more strongly to the
repolarization. For these reasons, the substances according to the
invention, which act as IKs blockers, have significant advantages
1 0 compared with the known IKr blockers. It has now also been described that
a correlation exists between IKs channel inhibitory action and the
suppression of life-threatening cardiac arrhythmias, such as are elicited, for
example, by 13-adrenergic hyperstimulation (e.g. T.J. Colatsky, C.H.
Follmer and C.F. Starmer; "Channel Specificity in Antiarrhythmic Drug
1 5 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 lll antiarrhythmics NE-10064 and NE-10133 inhibit
IsK channels in Xenopus oocytes and IKs in guinea pig cardiac myocytes";
Biochem. Biophys. Res. Commun.202 (1994), 265 - 270).
Moreover, the compounds I contribute to a marked improvement of cardiac
insufficiency, in particular of congestive heart failure, advantageously in
combination with contraction-promoting (positively inotropic) active
25 compounds, for example phosphodiesterase inhibitors.
In spite of the therapeutically utilizable advantages which can be achieved
by a blockade of the IKs, hitherto only very few compounds have been
described which inhibit this subtype of the "delayed rectifier". The
30 substance azimilide which is in development admittedly also has a blocking
action on the IKs, but mainly blocks the IKr (selectivity 1:10).
WO-A-95/14470 claims the use of benzodiazepines as selective blockers
CA 02230349 1998-02-24
of the IKs Further IKs blockers are described in FEBS Letters 396 (1996),
271 - 275: "Specific blockade of slowly activating IsK channels by
chromanols ..." and Pflugers Arch. - Eur. J. Physiol. 429 (1995), 517 - 530:
"A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon,
5 acting by the reduction of cAMP-activated K+ conductance". The potency
of the compounds mentioned there, however, is markedly 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
1 0 physiologically tolerable salts can thus be used in animals, preferably in
mammals, and in particular in humans as pharmaceuticals per se, in
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
1 5 the therapy and prophylaxis of the syndromes mentioned and their use for
the production of medicaments therefor and of medicaments with K+
channel-blocking action. Furthermore, the present invention relates to
pharmaceutical preparations which as active constituents contain an
effective dose of at least one compound of the formula I and/or of a
20 physiologically tolerable salt thereof in addition to customary,
pharmaceutically innocuous excipients and auxiliaries. The pharmaceutical
preparations normally contain 0.1 to 90% by weight of the compounds of
the formula I and/or their physiologically tolerable salts. The
pharmaceutical preparations can be prepared in a manner known per se.
25 For this purpose, the compounds of the formula I and/or their
physiologically tolerable salts, together with one or more solid or liquid
pharmaceutical excipients and/or auxiliaries and, if desired, in combination
with other pharmaceutical active compounds, are brought into a suitable
administration form or dosage form which can then be used as a
30 pharmaceutical in human medicine or veterinary medicine.
Pharmaceuticals which contain compounds of the formula I according to
CA 02230349 1998-02-24
38
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 course 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. Beside solvents, gel-forming agents, suppository bases, tablet
auxiliaries and other active compound carriers, it is possible to use, for
10 example, antioxidants, dispersants, emulsifiers, antifoams, flavor
corrigents, preservatives, solubilizers, agents for achieving a depot effect,
buffer substances or colorants.
The compounds of the formula I can also be combined with other
15 pharmaceutical active compounds to achieve an advantageous therapeutic
effect. Thus in the treatment of cardiovascular disorders, advantageous
combinations with substances having cardiovascular activity are possible.
Possible combination components of this type which are advantageous for
cardiovascular disorders are, for example, other antiarrhythmics, i.e.
20 class 1, class ll or class lll antiarrhythmics, such as, for example, IKr
channel blockers, e.g. dofetilide, or furthermore hypotensive substances
such as ACE inhibitors (for example enalapril, captopril, ramipril),
angiotensin antagonists, K+ channel activators, and also alpha- and beta-
receptor blockers, but also sympathomimetic compounds and compounds
25 having adrenergic activity, and also Na+/H+ 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
30 example with H2 antagonists (e.g. ranitidine, cimetidine, famotidine, etc.),
in particular when used for the treatment of gastrointestinal disorders.
CA 02230349 1998-02-24
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 means of the customary methods into the suitable
administration forms, such as tablets, coated tablets, hard capsules,
5 aqueous, alcoholic or oily solutions. Inert carriers which can be used are,
for example, gum arabic, magnesia, magnesium carbonate, potassium
phosphate, lactose, glucose or starc:h, in particular corn starch. In this case
the preparation can be carried out both as dry and as moist granules.
Suitable oily excipients or solvents are, for example, vegetable or animal
10 oils, such as sunflower oil or cod liver 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.
15 For subcutaneous or intravenous administration, the active compounds, if
desired with the substances customary therefor such as solubilizers,
emulsifiers or further auxiliaries, are brought into solution, suspension or
emulsion. The compounds of the formula I and their physiologically
tolerable salts can also be Iyophilized and the Iyophilizates obtained used,
20 for example, for the production of injection or infusion preparations.
Suitable solvents are, for example, water, physiological saline solution or
alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions
such as glucose or mannitol solutions, or alternatively mixtures of the
various solvents mentioned.
Suitable pharmaceutical formualtions 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,
30 ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as
surfactants, emulsifiers and stabilizers as well as a propellant. Such a
CA 02230349 1998-02-24
preparation customarily contains the active compound in a concentration
from approximately 0.1 to 10, in particular from approximately 0.3 to 3, %
by weight.
5 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, as customary, is to be adapted to the conditions of the individual case
for an optimum effect. Thus it depends, of course, on the frequency of
administration and on the potency and duration of action of the compounds
10 employed in each case 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
a compound of the formula I in the case of administration to a patient
approximately 75 kg in weight is 0.001 mg/kg of bodyweight to 100 mg/kg
of bodyweight, preferably 0.01 mg/kg of bodyweight to 20 mg/kg of
bodyweight. The dose can be administered in the form of an individual
dose or divided into several, e.g. two, three or four, individual doses. In
particular in the treatment of acute cases of cardiac arrhythmias, for
20 example in an intensive care unit, parenteral administration by injection or
infusion, e.g. by an intravenous continuous infusion, can also be
advantageous.
The compounds of the formula I and their physiologically tolerable salts
25 selectively inhibit K+(cAMP) channels and IKs channels. On account of this
property, apart from use as pharmaceutical active compounds in human
medicine and veterinary medicine, they can also be employed as a
scientific tool or as aids for biochemical investigations in which an effect on
potassium channels is intended, and also for diagnostic purposes, e.g. in
30 the in vitro diagnosis of cell or tissue samples. They can further be
employed, as already mentioned above, as intermediates for the
preparation of other pharmaceutical active compounds.
CA 02230349 l998-02-24
41
Experimental section
List of abbreviations
DMA N,N-Dimethylacetamide
DMSO Dimethyl sulfoxide
EA Ethyl acetate
m.p. Melting point [If not stated otherwise, the melting points of the
unpurified crude products are indicated; the melting points of
the respective pure substances can be quite markedly
higher].
NBS N-Bromosuccinimide
RT Room temperature
THF Tetrahydrofuran
Example 1: 3-Fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-
benzocycloheptene
O ~ r CH3
H / ~
-N O
F~)
a) 5 9 (28 mmol) of 8-fluoro-1-benzosuberone and 2.1 9 (31 mmol) of
hydroxylamine hydrochloride were heated under reflux for 5 h in 20 ml of
ethanol and 20 ml of pyridine. After distilling off the solvents on a rotary
evaporator, the residue was treated with water, adjusted to pH 2 using dil.
hydrochloric acid and stirred until the initially oily product crystallized. 5.1 9
of 8-fluoro-1-benzosuberone oxime (m.p. 97 - 103~C) were obtained, which
was reduced to 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene
by hydrogenation in methanol at normal pressure and RT using Raney
nickel as a catalyst. Yield: 4.3 g; m.p. of the hydrochloride 212 - 216~C.
CA 02230349 1998-02-24
42
b) 2.3 g (18 mmol) of ethanesulfonyl chloride were added dropwise with
ice-cooling to a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-
tetrahydro-5H-benzocycloheptene and 1.5 g (60 mmol) of triethylamine in
40 ml of THF. The mixture was allowed to come to room temperature and
5 was stirred overnight, and the solvent was distilled off in vacuo. After
stirring the residue with water, the precipitated product was filtered off with
suction. 2.9 g of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-
benzocycloheptene were obtained. M.p. 1 18 - 121~C.
1 O Example 2: 3-Fluoro-5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-
5H-benzocycloheptene
O ~ CH3
3 --N O
1 5 F ~
A solution of 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-
tetrahydro-5H-benzocycloheptene (Example 1) in 10 ml of DMA was added
dropwise under argon to a suspension of 0.12 g (4.1 mmol) of 80 percent
sodium hydride in 5 ml of DMA. After stirring at RT for 3 h, 0.63 g
(4.5 mmol) of methyliodide was added dropwise and the mixture was
stirred overnight at RT. After distilling off the solvent, the residue was
treated with water and extracted with EA. The organic phase was
concentrated in vacuo after drying over sodium sulfate. 0.64 g of 3-fluoro-
5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-
benzocycloheptene was obtained.
CA 02230349 1998-02-24
43
Example 3: 3-Fluoro-5-(N-ethylsulfonyl-N-butylamino)-6,7,8,9-tetrahydro-
5H-benzocycloheptene
O ~ CH3
H3C ~ N ~
F ~
From 0.12 g (4.1 mmol) of 80 percent sodium hydride, 0.81 g (3 mmol) of
1 0 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-
benzocycloheptene and 0.82 g (4.5 mmol) of butyliodide, 0.88 9 of
3-fluoro-5-(N-ethylsulfonyl-N-butylamino)-6,7,8,9-tetrahydro-5H-
benzocycloheptene was obtained analogously to Example 2.
1 5 Example 4: trans-7-Nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-
tetrahydro-1 -benzoxepin-4-ol
~ S CH3
H3C~,N/ o
\ + \ OH
O ~
o
a) 2,3-Dihydro-7-nitro-1-benzoxepine
10.2 g of sodium borohydride were added in portions at 0~C with vigorous
stirring to a suspension of 50 g of 3,4-dihydro-7-nitro-1-benzoxepin-5(2H)-
one (J. Chem. Soc., Perkin Trans.1, 1991, 2763) in 345 ml of methanol.
After 30 min, the reaction mixture was added to ice water, the solid was
hltered off with suction and 43 g of 7-nitro-2,3,4,5-tetrahydro-1 -benzoxepin-
5-ol was obtained. This was heated on a water separator for 2 h with 1 g of
p-toluenesulfonic acid in 520 ml of toluene. After cooling, the organic
phase was washed with sodium bicarbonate solution and sodium chloride
solution. After drying over sodium sulfate and concentrating, 38.8 g of 2,3-
CA 02230349 1998-02-24
dihydro-7-nitro-1 -benzoxepine were obtained . M .p. 98 - 1 00~C.
b) 4,5-Epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine
72.3 9 of NBS were added in one portion with ice-cooling to a solution of
38.8 9 of 2,3-dihydro-7-nitro-1-benzoxepine in 780 ml of DMSO and 78 ml
of water, the temperature rising to 30~C. After stirring at RT for 90 min, the
reaction mixture was poured into 5 1 of ice water and stirred for 1 h, the
crystalline precipitate was filtered off with suction and 60 9 of the
bromohydrin were obtained. A solution of this bromohydrin in 465 ml of
methanol was added dropwise at RT to a solution of 5.1 9 of sodium in
400 ml of methanol. After stirring for 1 h, the deposited precipitate was
filtered off with suction and washed with water. After drying, 37 9 of 4,5-
epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine were obtained. M.p. 123 -
1 25~C.
1 5
c) N-Methyl-N-trimethylsilylethanesulfonamide
A mixture of 33 9 of N-methylethanesulfonamide, 101 9 of
hexamethyldisilazane and a spatula tipful of ammonium chloride was
heated under argon, first for 2 h at 100~C and then for a further 1 h at
1 30~C. By distillation of the reaction mixture in vacuo, 42 9 of N-methyl-N-
trimethylsilylethanesulfonamide were obtained with the boiling point 118 -
121~C /10 mm Hg.
d) trans-7-Nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-
benzoxepin-4-ol
2 g of tetrabutylammonium fluoride were added with stirring to a mixture of
6 9 of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine and 9.5 9 of
N-methyl-N-trimethylsilylethanesulfonamide. The reaction mixture was then
heated for 3 h at 65~C, stirred overnight at RT and poured onto ammonium
chloride solution. It was extracted several times with EA, and the organic
phase was washed with water and dried over sodium sulfate. After
concentration and recrystallization of the solid residue from isopropanol,
CA 02230349 1998-02-24
7.1 g of trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-
1 -benzoxepin-4-ol were obtained. M.p. 133 - 135~C.
Example 5: trans-7-Cyano-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-
5 tetrahydro-1-benzoxepin-4-ol
~ CH3
~~S
3C N / O
N~ <OH
~ O
1.5 9 of tetrabutylammonium fluoride were added with stirring to a mixture
of 4 9 of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepine-7-carbonitrile
(J. Chem. Soc., Perkin Trans. 1, 1991, 2763) and 7.0 9 of N-methyl-N-
1 5 trimethylsilylethanesulfonamide. The reaction mixture was then heated for
3 h at 60~C, stirred overnight at RT and poured onto ammonium chloride
solution. It was extracted several times with EA, and the organic phase
was washed with water and dried over sodium sulfate. After concentration
and recrystallization of the solid residue from cyclohexane/EA (1 :5), 3.2 9
of trans-7-cyano-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-
benzoxepin-4-ol were obtained. M.p. 142 - 144~C.
Example 6: 5-(N-Ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-
benzoxepine
H ~~ ~CH3
N
~)
a) A solution of 10.0 9 (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one
(J. Chem. Soc., Perkin Trans. 1, 19'31, 2763) and 4.63 9 (68 mmol) of
CA 02230349 1998-02-24
46
hydroxylamine hydrochloride in 45 rnl of ethanol and 45 ml of pyridine was
heated under reflux for 5 h. After distilling off the solvents on a rotary
evaporator, the residue was treated with water, adjusted to pH 2 with dil.
hydrochloric acid and stirred for 3 h. After filtering off the precipitated
product with suction and drying it, 10.2 9 of 3,4-dihydro-1-benzoxepin-
5(2H)-one oxime were obtained. M.p. 96 - 98~C.
b) A solution of 2.0 9 (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one
oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0~C
under argon to a mixture of 4.5 9 (23.7 mmol) of titanium tetrachloride and
1.79 9 (47.4 mmol) of sodium borohydride in 50 ml of DME in the course of
20 min. After stirring at RT for 2 days, 100 ml of water were added
dropwise and the mixture was rendered alkaline using conc. ammonia
solution. After filtering off the precipitate with suction, the filtrate was
extracted three times with EA. After washing with sodium chloride solution,
drying over magnesium sulfate and concentrating, 2.1 9 of 5-amino-
2,3,4,5-tetrahydro-1-benzoxepine were obtained.
c) 0.86 9 (6.7 mmol) of ethanesulfonyl chloride was added dropwise with
ice cooling to a solution of 1.0 9 (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-
1-benzoxepine and 2.5 9 (24 mmol) of triethylamine in 20 ml of THF. The
mixture was allowed to come to room temperature and was stirred
overnight, and the solvent was distilled off in vacuo. After stirring the
residue with water, the deposited product was filtered off with suction. 1.1 9
of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained.
M.p. 109- 111~C.
d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-
1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a
suspension of 0.16 9 (5.4 mmol) of 80 percent sodium hydride in 10 ml of
THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were
added dropwise and the mixture was additionally stirred overnight at RT.
CA 02230349 1998-02-24
47
After distilling off the solvent, the residue was treated with water and
extracted with EA. The organic phase was concentrated in vacuo after
drying over sodium sulfate. 1.0 9 of 5-(N-ethylsulfonyl-N-methylamino)-
2,3,4,5-tetrahydro-1-benzoxepine was obtained. M.p. 122 - 124~C.
Example 7: 5-(N-Butyl-N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-
benzoxepine
\~_ ~"S~
-N 0
From 7.1 9 of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine
(Example 6 c), 8.3 9 of 5-(N-butyl-N-ethylsulfonylamino)-2,3,4,5-tetrahydro-
1-benzoxepine were obtained by alkylation with butyl iodide analogously to
Example 11 as a viscous oil which crystallized after a relatively long time.
M.p. 62 - 65~C.
Example 8: 5-(N-Methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-
benzoxepine
~"S/
---N' 0
[~
a) 1.54 9 (13.4 mmol) of methanesulfonyl chloride were added dropwise
with ice cooling to a solution of 2.0 9 (12.2 mmol) of 5-amino-2,3,4,5-
tetrahydro-1-benzoxepine (Example 6 b) and 3.7 9 (36.6 mmol) of
30 triethylamine in 40 ml of THF. The mixture was allowed to come to RT and
was stirred overnight and treated with 50 ml of water, and the THF was
distilled off in vacuo. The residue was diluted with a further 50 ml of water
CA 02230349 1998-02-24
48
and stirred for 3 h, and the deposited product was filtered off with suction.
After drying in vacuo, 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-
benzoxepine were obtained. M.p. 105 - 1 06~C.
b) A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-
tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a
suspension of 0.23 g (6.2 mmol) of 80 percent sodium hydride in 10 ml of
THF. After 2 h at RT, 0.94 g (6.7 mmol) of iodomethane were added and
the mixture was stirred overnight at RT. After distilling off the solvent in
vacuo, the residue was taken up in EA, and the solution was washed with
dil. hydrochloric acid and water, dried over magnesium sulfate and
concentrated. Subsequent recrystallization of the product from isopropanol
yielded 0.5 g of 5-(N-methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-
benzoxepine. M.p. 143-145~C.
1 5
Example 9: 5-(N-Butyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-
benzoxepine
O /
S
~--N 0
1.0 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine
25 (Example 8 a) were reacted with sodium hydride and iodobutane in DMF
analogously to Example 11. After recrystallization of the crude product
(1.0 g) from isopropanol, 0.4 g of 5-(N-butyl-N-methylsulfonylamino)-
2,3,4,5-tetrahydro-1-benzoxepine was obtained. M.p. 78 - 79~C.
CA 02230349 1998-02-24
49
Example 10: 7-Chloro-9-methyl-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-
tetrahyd ro- 1 -benzoxepine
~,
---N/ "O
Cl~
a) A mixture of 90 9 of 4-(4-chloro-2-methylphenoxy)butyric acid (Aldrich)
and 1000 9 of polyphosphoric acid was stirred for 4.5 h at 85~C. The batch
was then poured onto 51 of ice water, stirred for 1 h and extracted with
ether. The combined organic phases were washed several times with
sodium carbonate solution and water, dried over magnesium sulfate and
concentrated in a rotary evaporator. The dark residue was then taken up in
ether again and boiled several times with active carbon and silica gel, and
filtered until the solution was only slightly colored. After concentrating,
48.4 g of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one were
obtained; m.p.: 56 - 58~C.
b) 3.0 9 of 7-chloro-9-methyl-3,4-dihydro-2H-1-benzoxepin-5-one, 50 ml of
anhydrous methanol, 10.9 9 of ammonium acetate and 0.63 9 of sodium
cyanoborohydride were stirred for 5 h at 60~C and then for 2 days at RT.
The reaction mixture was then acidified with hydrochloric acid and then
concentrated on a rotary evaporator. The residue was taken up in water,
and the solution was rendered alkaline with ammonia solution and
extracted with ethyl acetate. After drying and concentrating, the product
was purified by chromatography on silica gel using ethyl acetate/methanol
9:1 and 1.3 9 of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-
benzoxepine were obtained.
c) 0.86 9 of ethanesulfonyl chloride was added dropwise with ice-cooling to
a solution of 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-
CA 02230349 1998-02-24
benzoxepine and 2.4 9 of triethylamline in 30 ml of THF. The mixture was
allowed to come to room temperature and was stirred overnight, and the
solvent was distilled off in vacuo. After stirring the residue with water, the
deposited product was filtered off with suction and dried in vacuo. 1.6 9 of
7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-
benzoxepine were obtained; m.p. 144 - 145~C.
d) A solution of 0.6 9 (2.0 mmol) of 7-chloro-9-methyl-5-(N-
ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine in 8 ml of THF was
added dropwise under nitrogen to a suspension of 0.1 9 (2.7 mmol) of
80 percent sodium hydride in 5 ml of THF. After stirring at RT for 1 h,
0.41 g (2.9 mmol) of methyl iodide was added dropwise and the mixture
was additionally stirred overnight at RT. After distilling off the solvent, the
residue was treated with water and extracted with EA. After washing the
organic phase with dil. hydrochloric acid and water, and drying over
magnesium sulfate, it was concentrated in vacuo and the crude product
was recrystallized from methylene chloride. 0.4 9 of 7-chloro-9-methyl-5-
(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was
obtained; m.p.: 141-143~C.
1 H-NMR (CDCI3): ~ [ppm] = 1.35 (3H), 1.9-2.2 (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
~ ~~S/~
--N 0
Cl~
A solution of 0.8 9 (2.6 mmol) of 7-chloro-9-methyl-5-(N-
CA 02230349 1998-02-24
51
ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10 c) in
10 ml of DMF was added dropwise under nitrogen to a suspension of 0.1 g
(2.7 mmol) of 80 percent sodium hydride in 8 ml of DMF. After stirring at
RT for 30 min, 0.68 g (3.7 mmol) of butyl iodide was added dropwise and
5 the mixture was additionally stirred overnight at RT. After distilling off thesolvent, the residue was treated with water and extracted with EA. After
washing the organic phase with dil. hydrochloric acid in water, and drying
over magnesium sulfate, it was concentrated in vacuo. 0.9 g of 5-(N-butyl-
N-ethylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1 -benzoxepine
1 0 was obtained; m.p. 83 - 87~C.
Example 12: 5-(N-Butyl-N-methylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-
tetrahydro-1 -benzoxepine
1 5 \~ ,S
Cl
~\o~
0.6 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine
(Example 10 b) were reacted with methanesulfonyl chloride analogously to
Example 10 c. 0.6 9 of 7-chloro-9-methyl-5-methylsulfonylamino-2,3,4,5-
tetrahydro-1 -benzoxepine was obtained; m.p.: 154 - 156~C. By subsequent
alkylation with butyl iodide analogously to Example 11, 0.6 9 of 5-(N-butyl-
N-methylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1 -
benzoxepine was obtained; m .p.: 106 - 110~C.
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52
Example 13: 5-(N-Butyl-N-methylsulfonylamino)-7-nitro-2,3,4,5-tetrahydro-
1 -benzoxepine
~ O~ /
~ N,S~0
, N
a) 10.0 g (61.7 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem.
1 0 Soc., Perkin Trans. 1, 1991, 2763) were introduced into 80 ml of conc.
sulfuric acid with ice cooling. 5.77 g (67.9 mmol) of sodium nitrate were
then added and the mixture was stirred for 90 min at 0~C. The reaction
mixture was poured onto 800 ml of water, and the deposited product was
filtered off with suction, washed until it was neutral and dried in vacuo.
1 5 After recrystallization from isopropanol, 7 g of 3,4-dihydro-7-nitro-1-
benzoxepin-5(2H)-one which was contaminated with about 12% of the
corresponding 7,9-dinitro compound were obtained. M.p. 112 - 116~C.
b) 3.4 g (16.4 mmol) of 3,4-dihydro-7-nitro-1-benzoxepin-5(2H)-one were
stirred for 3 h at 60~C with 12.7 9 (164 mmol) of ammonium acetate and
7.2 g (115 mmol) of sodium cyanoborohydride in 55 ml of methanol. After
addition of 10 ml of water, the batch was concentrated in vacuo and the
residue was taken up in ethyl acetate and washed with dil. sodium
hydroxide solution. The EA phase was extracted with dil. hydrochloric acid
and the hydrochloric acid phase obtained was rendered alkaline with
sodium hydroxide solution and extracted with EA. After drying the EA
extract, 1.7 g of 5-amino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine were
obtained.
c) From 1.6 9 of 5-amino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine,1.9 g of
5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1 -benzoxepine were
obtained analogously to Example 8 a. M.p. 150 - 151 ~C.
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53
d) From 0.5 9 of 5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1-
benzoxepine 0.6 9 of 5-(N-butyl-N-methylsulfonylamino)-7-nitro-2,3,4,5-
tetrahydro-1-benzoxepine were obtained by reaction with sodium hydride
and iodobutane in DMF analogously to Example 11. M.p. 96 - 98~C.
Example 14: 7-Butoxy-3,4-dihydro-2H-1-benzoxepin-5-one
O
~ \~ /
~N 'o
~~~
a) From 4-butoxyphenol, 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one can
15 be obtained by alkylation with ethyl 4-bromobutyrate, followed by
hydrolysis and cyclization in the presence of polyphosphoric acid, as
described in J. Heterocyclic Chem. 26, 1989, 1547 for the analogous
7-propoxy-3,4-dihydro-2H-1 -benzoxepin-5-one.
b) From 7-butoxy-3,4-dihydro-2H-1-benzoxepin-5-one, 7-butoxy-3,4-
dihydro-2H-1-benzoxepin-5-one can be obtained by reductive amination
with ammonium acetate and sodium cyanoborohydride followed by
reaction with methanesulfonyl chloride and finally alkylation with butyl
iodide, as described in Example 13 b - d.
Pharmacological investigations
IsK channels from man, rat or guinea-pig were expressed in Xenopus
oocytes. To do this, oocytes were first isolated from Xenopus laevis and
defolliculated. IsK-encoding RNA synthesized in vitro was then injected
into these oocytes. After IsK protein expression for 2 - 8 days, ISK currents
were measured in the oocytes using the two microelectrode voltage clamp
technique. The IsK channels were in this case as a rule activated using
CA 02230349 1998-02-24
54
voltage jumps to -10 mV lasting 15 s. The bath was irrigated with a solution
of the following composition: NaCI 96 mM, KCI 2 mM, CaCI2 1.8 mM,
MgCI2 1 mM, HEPES 5 mM (titrated with NaOH to pH 7.5). These
experiments were carried out at room temperature. The following were
5 employed for acquiring data and analysis: Geneclamp amplifier (Axon
Instruments, Foster City, USA) and MacLab D/A converter and software
(ADlnstruments, Castle Hill, Australia). The substances according to the
invention were tested by adding them to the bath solution in different
concentrations. The effects of the substances were calculated as the
10 percentage inhibition of the IsK control current, which was obtained when
no substance was added to the solution. The data were then extrapolated
using the Hill equation in order to determine the inhibitory concentrations
IC50 for the respective substances.
1 5 References:
A.E. Busch, H.-G. Kopp, S. Waldegger, l. Samarzija, H. Sul3brich,
G. Raber, K. Kunzelmann, J. P. Ruppersberg and F. Lang; "Inhibition of
both exogenously expressed IsK and endogenous K+ channels in
Xenopus oocytes by isosorbide dinitrate"; J. Physiol. 491 (1995), 735-741;
20 T. Takumi, H. Ohkubo and S. Nakanishi; "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 mediates
25 species-specific responses to protein kinase"; C. Proc. Natl. Acad. Sci.
USA 90 (1993), 11528-11532.
For the compound of Example 13, an IC50 value of 3.3 I~mol I I was
determined in the manner described.
