Heteroarylacryloylaminoalkyl-substituted benzenesulfonamide...

Details Heteroarylacryloylaminoalkyl-substituted benzenesulfonamide... Heteroarylacryloylaminoalkyl-substituted benzenesulfonamide...

2001-11-02

2002-10-29

Davis, Zinna Northington (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S337000, C549S077000, C514S438000

Reexamination Certificate

active

06472413

ABSTRACT:

This application claims the benefit of the filing date of German Patent Application Number 10054482.7, filed on Nov. 3, 2000, which application is hereby incorporated by reference.
One embodiment of the present invention relates to heteroarylacryloylaminoalkyl-substituted benzenesulfonamide derivatives of the formula (I),
in which R(1), R(2), R(3), R(4), Het, X, Y and Z have the meanings indicated below. The compounds of the formula (I) are valuable pharmaceutically active compounds that have, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the vagal cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, cardiomyopathies, decreased contractility of the heart or vagal dysfunction of the heart, or for the prevention of sudden cardiac death. Another embodiment of the invention relates to processes for the preparation of compounds of the formula (I), their use and pharmaceutical preparations comprising them.
For certain benzenesulfonylureas, a blood-sugar-lowering action has been described. A prototype of such blood-sugar-lowering sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus. 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 blood-sugar-lowering action, glibenclamide has other actions that are attributed to the blockade of precisely these ATP-sensitive potassium channels but that hitherto can still not be used therapeutically. These include, for example, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide however, the marked blood-sugar-lowering simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient, so that glibenclamide is not suitable clinically as an antiarrhythmic.
Various patent documents, for example U.S. Pat Nos. 5,574,069, 5,698,596, 5,476,850, 5,652,268 or WO-A-00/03978, disclose antifibrillatory benzenesulfonylureas and -thioureas having reduced blood-sugar-lowering action. WO-A-00/15204 describes the action of some of these compounds on the autonomic nervous system. The properties of these compounds, however, are still not satisfactory in various respects, and there is an ongoing need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile that are better suited, for example, for the treatment of a disturbed cardiac rhythm and its consequences such as sudden cardiac death or a weakened myocardial contractile force.
Various benzenesulfonylureas having an acylaminoalkyl substituent, in which the acyl group can also be derived, inter alia, from cinnamic acids, and the blood-sugar-lowering action of these compounds are disclosed in DE-A-1443878, U.S. Pat. No. 3,454,636, DE-A-1518877 and U.S. Pat. No. 4,066,639. The benzenesulfonylureas that are described in GB-A-1116355 are just so characterized by a blood-sugar-lowering action, among them some specific benzenesulfonylureas that contain a heteroarylacryloyl-aminoalkyl group in the para position to the sulfonylurea group. In WO-A-00/71513 (international patent application PCT/EP00/04091) certain cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives are described, which are distinguished by a marked action on ATP-sensitive potassium channels in the heart. Further investigations showed that the benzenesulfonamide derivatives of the present invention, which contain a heteroarylacryloylaminoalkyl substituent in the meta position to the sulfonyl group, show a marked action on ATP-sensitive potassium channels of the cardiac muscle and/or of the vagal cardiac nerve, without having a marked action on pancreatic potassium channels and thus are valuable pharmaceutically active compounds, for example, for the treatment of disorders of the cardiovascular system.
Another embodiment of the present invention relates to compounds of the formula (I),
in which
R(1) is
1) (C
1
-C
4
)-alkyl; or
2) —O—(C
1
-C
4
)-alkyl, which is unsubstituted or is substituted by 1, 2, or 3 fluorine atoms; or
3) —O—(C
1
-C
4
)-alkyl, which is substituted by a substituent chosen from nitro, ((C
1
-C
4
)-alkyl)carbonylamino, (C
1
-C
4
)-alkylamino, di((C
1
-C
4
)-alkyl)amino, hydroxycarbonyl, ((C
1
-C
4
)-alkoxy)carbonyl, piperidin-1-yl, morpholin4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and phenoxy; where the phenyl group and the phenoxy group are unsubstituted or are substituted by one or two identical or different substituents chosen from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl; or
4) —O—(C
1
-C
4
)-alkyl-E(1)-(C
1
-C
4
)-alkyl-D(1), in which D(1) is hydrogen —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; or
5) —O—(C
1
-C
4
)-alkyl-O—(C
1
-C
4
)-alkyl, which is substituted by 1, 2 or 3 fluorin atoms; or
6) —O—(C
2
-C
4
)-alkenyl; or
7) —O-phenyl which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl; or
8) halogen; or
9) phenyl, which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C
1
—C
4
)-alkyl, (C
1
-C
4
)-alkoxy, -S(O)
m
—(C
1
-C
4
)-alkyl, phenyl, amino, hydroxyl, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, ((C
1
-C
4
)-alkoxy)carbonyl, and formyl; or
10) (C
2
-C
5
)-alkenyl, which is unsubstituted or is substituted by a substituent chosen from phenyl, cyano, hydroxycarbonyl, and ((C
1
-C
4
)-alkoxy)carbonyl; or
11) (C
2
-C
5
)-alkynyl, which is unsubstituted or is substituted by a substituent chosen from phenyl and (C
1
-C
4
)-alkoxy; or
12) 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms chosen from oxygen, sulfur, and nitrogen; or
13) —S(O)
m
-phenyl which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, and trifluoromethyl;
R(2) is hydrogen or (C
1
-C
6
)-alkyl, 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 hydrogen or (C
1
-C
4
)-alkyl;
the residues R(5), which are all independent of one another and can be identical or different, are hydrogen or (C
1
-C
3
)-alkyl;
Het is 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms chosen from oxygen, sulfur, and nitrogen, which is unsubstituted or is substituted by one or two identical or different substituents chosen from halogen, nitro, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy and trifluoromethyl;
X is oxygen or sulfur;
Y is —(CR(5)
2
)
n
—;
Z is NH or oxygen;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
If groups, residues, substituents or variables can occur several times in the compounds of the 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 groups derived therefrom such as, for example, alkoxy, alkoxycarbonyl, or the residue —S(O)
m
-alkyl. Examples of alkyl residues include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-methyl-butyl, isopentyl, neopentyl, tert-pentyl, n-hexyl or isohexyl. Examples of alkoxy include methoxy, ethoxy, propoxy such as n-propoxy and isopropoxy, butoxy such as n-butoxy, isobutoxy, and tert-butoxy, etc. The same applies correspondingly to s

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