Sulfonamide-substituted fused 7-membered ring compounds,...

Details Sulfonamide-substituted fused 7-membered ring compounds,... Sulfonamide-substituted fused 7-membered ring compounds,...

1999-06-29

2001-12-25

Ghah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S337000, C514S601000, C514S602000, C514S603000, C514S604000, C514S605000, C546S281700, C549S355000, C564S080000, C564S081000, C564S082000, C564S084000, C564S085000, C564S086000, C564S087000, C564S089000, C564S090000, C564S091000, C564S092000, C564S095000, C564S096000, C564S097000, C564S099000

Reexamination Certificate

active

06333349

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds of formula I,
in which X1, X2, X3, X4, Y1, Y2, Y3, Y4, R(3), R(4) and R(5) have the meanings in the following, their preparation and their use, in particular in pharmaceuticals. The compounds affect the potassium channel opened by cyclic adenosine monophosphate (cAMP) or the I
Ks
channel and are outstandingly suitable as pharmaceutical active compounds, for example for the prophylaxis and therapy of cardiovascular disorders, in particular arrhythrnias, for the treatment of ulcers of the 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 of the formula A, an example of a homolog is the compound of the formula B (
J. Chem. Soc., Perkin Trans
. 1 (1991), 2763).
Cromakalim and other related 4-acylaminochroman derivatives are 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 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 Ca
2+
concentration and thus cell activation, which leads, for example, to muscle contraction.
The compounds of formula I according to the invention differ structurally from these acylainino derivatives, in particular by the replacement of the acylamino group by a sulfonylamino function. While 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 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 (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) channel identified in colonic tissue is very similar, perhaps even identical, to the I
Ks
channel identified in the cardiac muscle. In fact, it was possible for the compounds of formula I according to the invention to show a strong blocking action on the I
Ks
channel in guinea-pig cardiomyocytes and on the I
Ks
channel expressed in Xenopus oocytes. As a result of this blockage of the K
+
(cAMP) channel or of the I
Ks
channel, the compounds according to tie 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 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 formula I
in which:
X1 is —O—, —S—, —SO—, —SO
2
—, —CR(1)R(2)—, —NR(6)—, —CO— or —CR(1)R(7)—;
R(1) and R(2)
independently of one another are hydrogen, CF
3
, C
2
F
5
, C
3
F
7
, 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, CF
3
, NO
2
, CN, NH
2
, 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 —C
n
H
2n
—R(8),
where a CH
2
group of the group C
n
H
2n
can be replaced by —O—, —CH═CH—, —C≡C—, —CO—, —CO—O—, —O—CO—, —S—, —SO—, —SO
2
—, —NR(9)— or —CONR(9)—;
R(9) is 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, CF
3
, C
2
F
5
, C
3
F
7
, 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, CF
3
, NO
2
, CN, NH
2
, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and metlylsulfonylamino;
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—, —SO
2
— 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—, —SO
2
— 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) together with 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, CF
3
, C
2
F
5
, C
3
F
7
, N
3
, NO
2
, —Z—C
m
H
2m
—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, CF
3
, NO
2
, CN, NH
2
, OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
Z is —O—, —CO—, —CO—O—, —O—CO—, —S—, —SO—, —SO
2
—, —SO
2
NR(14)—, —NR(14)— or —CONR(14)—;
R(14) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
m is zero, 1, 2, 3, 4, 5 or 6;
R(13) is hydrogen, CF
3
, C
2
F, C
3
F
7
, 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, CF
3
, NO
2
, CN, NH
2
, 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 CH
2
group can be replaced by —O—, —S—, —NH—, —N(CH
3
)— or —N(benzyl)—;
R(30a)
is hydrogen, alkyl having 1, 2 or 3 carbon atoms or acyl having 1, 2, 3 or 4 carbon atoms; or
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 as defined for Y1, Y2, Y3, Y4;
R(3) is R(17)—C
x
H
2x
—NR(18)— or R(17)—C
x
H
2x

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