Cinnamoylaminoalkyl-substituted benzenesulfonamide...

Details Cinnamoylaminoalkyl-substituted benzenesulfonamide... Cinnamoylaminoalkyl-substituted benzenesulfonamide...

2000-05-19

2002-02-26

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S478000, C514S584000, C514S593000, C514S604000, C549S496000, C560S013000, C564S027000, C564S040000, C564S086000

Reexamination Certificate

active

06350778

ABSTRACT:

The present invention relates to cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives of formula I
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), X, Y, and Z have the meanings indicated below. Compounds of formula I are valuable pharmaceutical active compounds which exhibit, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, or cardiomyopathies, or for the prevention of sudden cardiac death or for improving decreased contractility of the heart. The invention furthermore relates to processes for the preparation of compounds of formula I, their use, and pharmaceutical preparations comprising them.
A hypoglycemic action is described for certain benzenesulfonylureas. Glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus, counts as a prototype of hypoglycemic sulfonylureas of this type. Glibenclamide blocks ATP-sensitive potassium channels and is used in research as a tool for the exploration of potassium channels of this type. In addition to its hypoglycemic action, glibenclamide additionally possesses other actions that are attributed to the blockade of precisely these ATP-sensitive potassium channels, which as yet, however, still cannot be utilized therapeutically. These include, in particular, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide, however, the marked hypoglycemia simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient.
Various patent applications, for example U.S. Pat. No. 5,698,596, U.S. Pat. No. 5,476,850, or U.S. Pat. No. 5,652,268 and WO-A-00/03978 (German Patent Application 19832009.4), disclose antifibrillatory benzenesulfonylureas and -thioureas having decreased hypoglycemic action. WO-A-00/15204 (German Patent Application 19841534.6) describes the action of some of these compounds on the autonomic nervous system. The properties of these compounds, however, are not satisfactory in various respects, and there furthermore exists a need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile, which are better suited, in particular, to the treatment of a disturbed heart rhythm and its consequences. Various benzenesulfonylureas having an acylaminoalkyl substituent in which the acyl group can also be derived, inter alia, from cinnamic acids, are disclosed in German Laid-Open Specifications DE-A-1443878, DE-A-1518816, DE-A-1518877, and DE-A-1545810. These compounds have a hypoglycemic action, but an action on the heart is not known as yet. Surprisingly, it has now been found that certain cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives are distinguished by a marked action on ATP-sensitive potassium channels in the heart and further advantageous pharmacological actions.
One subject of the present invention are compounds of formula I
in which:
X is oxygen, sulfur, or cyanoimino;
Y is —(CR(5)
2
)
n
—;
Z is NH or oxygen;
the residues A(1), A(2), and A(3), which are independent of one another and can be identical or different, are hydrogen, halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, methylenedioxy, formyl, or trifluoromethyl;
R(1) is
a) (C
1
-C
4
)-alkyl;
b) —O—(C
1
-C
4
)-alkyl;
c) —O—(C
1
-C
4
)-alkyl—E(1)—(C
1
-C
4
)-alkyl-D(1), in which D(1) is hydrogen or —E(2)—(C
1
-C
4
)-alkyl-D(2), in which D(2) is hydrogen or —E(3)—(C
1
-C
4
)-alkyl, where E(1), E(2), and E(3), which are independent of one another and can be identical or different, are O, S, or NH;
d) —O—(C
1
-C
4
)-alkyl which is substituted by a residue of a saturated 4-membered to 7-membered heterocycle which contains one or two oxygens as ring heteroatoms;
e) —O—(C
2
-C
4
)-alkenyl;
f) —O—(C
1
-C
4
)-alkyl-phenyl in which the phenyl group is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl;
g) —O-phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl;
h) halogen;
i) phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, —S(O)
m
—(C
1
-C
4
)-alkyl, phenyl, amino, hydroxy, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, (C
1
-C
4
)-alkoxycarbonyl, and formyl;
j) (C
2
-C
5
)-alkenyl which is unsubstituted or substituted by a substituent selected from phenyl, cyano, hydroxycarbonyl, and (C
1
-C
4
)-alkoxycarbonyl;
k) (C
2
-C
5
)-alkynyl which is unsubstituted or substituted by a substituent selected from phenyl and (C
1
-C
4
)-alkoxy;
l) monocyclic or bicyclic heteroaryl having one or two identical or different ring heteroatoms selected from oxygen, sulfur, and nitrogen;
m) —S(O)
m
-phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl; or
n) —S(O)
m
—(C
1
-C
4
)-alkyl;
R(2) is hydrogen, (C
1
-C
6
)-alkyl, or (C
3
-C
7
)-cycloalkyl, but is not hydrogen if Z is oxygen;
the residues R(3) and R(4), which are independent of one another and can be identical or different, are phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl, hydrogen, or (C
1
-C
4
)-alkyl;
the residues R(5), which are independent of one another and can be identical or different, are hydrogen or (C
1
-C
3
)-alkyl;
m is 0, 1, or2;
n is 1, 2, 3, or 4;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof,
where compounds of formula I are excluded in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C
1
-C
4
)-alkyl, or —O—(C
1
-C
4
)-alkyl, and R(2) is (C
2
-C
6
)-alkyl or (C
5
-C
7
)-cycloalkyl.
If groups, residues, substituents, or variables can occur several times in compounds of formula I, they can all independently of one another have the meanings indicated and can in each case be identical or different.
The term alkyl denotes straight-chain or branched saturated hydrocarbon residues. This also applies to residues derived therefrom such as, for example, alkoxy, alkoxycarbonyl, or the residue —S(O)
m
-alkyl. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, or isohexyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, or tert-butoxy. The same applies to substituted alkyl residues, for example phenyl-alkyl- residues, or to divalent alkyl residues (alkanediyl residues), in which the substituents or the bonds via which the residues are bonded to the neighboring groups can be situated in any desired positions. Examples of alkyl residues of this type, which are bonded to two neighboring groups and which, inter alia, can represent the group Y, are —CH
2
—, —CH(CH
3
)—, —C(CH
3
)
2
—, —CH
2
—CH
2
—, —CH(CH
3
)—CH
2
—, —CH
2
—CH(CH
3
)—, —CH
2
—CH
2
—CH
2
—, or —CH
2
—CH
2
—CH
2
-CH
2
—.
Alkenyl and alkynyl denote straight-chain or branched, mono- or polyunsaturated hydrocarbon residues, in which the double bonds and/or triple bonds can be situated in any desired positions. Preferably, the residues alkenyl and alkynyl contain one double bond or one triple bond. Examples of alkenyl and alkynyl are vinyl, prop-2-enyl (allyl), prop-1-enyl, but-2-enyl, but-3-enyl, 3-methylbut-2-enyl, pent-2,4-dienyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl, and but-3-ynyl. In substituted alkenyl residues and alkynyl residues, the substituents can be situated in any desired positions.
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