Sulfonamide-substituted compounds, processes for their...

Details Sulfonamide-substituted compounds, processes for their... Sulfonamide-substituted compounds, processes for their...

1998-08-04

2001-02-06

Kight, John (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S234200, C514S234500, C514S249000, C514S253030, C514S257000, C514S302000, C514S318000, C514S321000, C514S326000, C514S443000, C514S444000, C514S445000, C544S116000, C544S122000, C544S127000, C544S129000, C544S139000, C544S146000, C544S230000, C544S235000, C544S278000, C544S350000, C544S364000, C546S018000, C546S113000, C546S198000, C546S202000, C546S207000, C546S282100, C549S050000, C549S051000, C549S052000, C549S058000

Reexamination Certificate

active

06184221

ABSTRACT:

The present case claims priority of German Patent Application 19733779.1, filed Aug. 5, 1997, and German Patent Application 19747889.1, filed Oct. 30, 1997, both of which are incorporated by reference.
DESCRIPTION
The invention relates to compounds of the formula I
in which R(1), R(2), R(3), R(4), R(5), R(6), R(7) and R(8) have the meanings indicated 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 arrhythmias, for the treatment of ulcers of the gastrointestinal region or for the treatment of diarrheal illnesses.
In pharmaceutical chemistry, the 4-acylaminochroman derivatives class has been worked on intensively in recent years. The most prominent representative of this class is cromakalim of the formula A (J. Chem. Soc. Perkin Trans. 1, 1991, 63-70).
Cromakalim and other related 4-acylaminochroman derivatives are compounds having a relaxant action on smooth muscular organs, so 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 an 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.
Similar structures to those of the formula I, the so-called pyranopyridines (formula B), are described in the literature. However, we are also dealing here exclusively with 4-acylamino derivatives, which likewise have K-ATP channel-blocking properties.
The compounds of the formula I according to the invention differ structurally from these acylamino derivatives, 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
+
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 (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 the formula I according to the invention, to show a strong blocking action on the I
Ks
channel in guinea-pig cardio-myocytes and on the I
sK
channel expressed in Xenopus oocytes. As a result of this blocking of the K
+
(cAMP) channel or of the I
Ks
channel, the compounds according to the invention display pharmacological actions of high therapeutic utility in the living body.
The present invention relates to compounds of the formula I
in which:
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,
wherein said phenyl is unsubstituted or substituted by 1 or 2 identical or different substituents that are F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, or methylsulfonyl;
or
R(1) and R(2) together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;
where one CH
2
group of the alkylene chain can be replaced by —O—, —CO—, —S—, —SO—, —SO
2
—, or —NR(10)—;
R(10) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
R(3) is R(12)—C
a
H
2a
[NR(13)]
m
—;
R(12) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, CF
3
, C
2
F
5
, or C
3
F
7
;
a is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m is zero or 1;
R(13) is hydrogen or alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms;
or
R(12) and R(13) together are an alkylene chain having 4, 5, 6, 7, or 8 carbon atoms, where one CH
2
group of the alkylene chain can be replaced by —O—, —[SO
zero, 1, or 2
]—, —CO—, or —NR(10)—;
R(10) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
R(4) is R(14)—C
r
H
2r
;
r is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
R(14) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF
3
, C
2
F
5
, C
3
F
7
, pyridyl, thienyl, imidazolyl, or phenyl,
wherein said phenyl is unsubstituted or substituted by 1 or 2 identical or different substituents that are F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, methylsulfonyl, or methylsulfonylamino;
where one CH
2
group of the group C
r
H
2r
can be replaced by —O—, —CH═CH—, —C≡C—, —CO—, —CO—O—, —CO—NR(11)—, —[SO
zero, 1, or 2
]—, or —NR(11)—;
R(11) is hydrogen or —(C
a
H
2a
)—R(10);
where one CH
2
group of the group C
a
H
2a
can be replaced by —O—, —CH═CH—, —C≡C—, —CO—, —CO—O—, —O—CO—, —S—, —SO—, —SO
2
—, —NR(10)—, or —CONR(10)—;
R(10) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
a is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
or
R(3) and R(4) together are an alkylene chain having 3, 4, 5, 6, 7, or 8 carbon atoms, where one CH
2
group of the alkylene chain can be replaced by —O—, —[SO
zero, 1, or 2
]—, —CO—, or —NR(11)—;
R(11) is hydrogen or —(C
a
H
2a
)—R(10), where one CH
2
group of the group C
a
H
2a
can be replaced by —O—, —CH═CH—, —C≡C—, —CO—, —CO—O—, —O—CO—, —S—, —SO—, —SO
2
—, NR(10)—, or —CONR(10)—;
R(10) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
a is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R(5) and R(6) are
—CR(15)═CR(16)—CR(17)═N—,
—CR(15)═CR(16)—N═CR(17)—,
—CR(15)═N—CR(17)═N—,
—CR(15)═N—N═CR(17)—,
—N═CR(16)—CR(17)═N—, or
—S—CR(15)═CR(16)—;
R(15), R(16) and R(17) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, or 4 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
, —CONR(19)R(21), —COOR(21), R(22)—C
s
H
2s
—Z—, or phenyl,
wherein said phenyl is unsubstituted or substituted by 1 or 2 identical or different substituents that are F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, or methylsulfonyl;
R(19) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
R(21) is hydrogen, methyl, ethyl, phenyl, or —C
u
H
2u
—NR(19)R(20);
wherein said phenyl is unsubstituted or substituted by 1 or 2 identical or different substituents that are F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, or methylsulfonyl;
R(20) is hydrogen or alkyl having 1, 2, or 3 carbon atoms;
u is 2 or 3;
R(22) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, —COOR(21), CONR(19)R(21), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF
3
, C
2
F
5
, C
3
F
7
, or phenyl,
wherein said phenyl is unsubstituted or substituted by 1 or 2 identical or different substituents that are F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, or methylsulfonyl;
s is zero, 1, 2, 3, 4, 5, or 6;
Z is —[S(O)
zero, 1, or 2
]—, —CO—, —SO
(zero, 1, or 2)
—NR(11)—, —SO
2
—O—, —O—, —NR(11)—, or —[CO—NR(11)]—;
R(7) is hydrogen, hydroxyl, alkoxy having 1, 2, 3, or 4 carbon atoms, acyloxy having 1, 2, 3, or 4 carbon atoms, Cl, Br, F, or alkyl having 1, 2, 3, or 4 carbon atoms;
R(8) is hydrogen or alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms;
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which:
R(1) and R(2) independently of one another a

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