Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-11-09
2002-07-02
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S586000, C514S592000, C514S593000, C514S821000
Reexamination Certificate
active
06414030
ABSTRACT:
Use of benzenesulfonyl(thio)ureas for the treatment and prophylaxis of dysfunctions of the autonomous nervous system and use of benzenesulfonyl(thio)ureas in combination with beta-receptor blockers.
This application claims the benefit of priority to German patent applications serial No. 19841534.6, filed Sep. 10, 1998, and serial No. 19901061.7, filed Jan. 14, 1999. Both applications are incorporated by reference herein.
Substituted benzenesulfonylureas and -thioureas of the formula I
in which R
1
, R
2
, E, X, Y and Z have the meanings given below, show effects on the autonomous nervous system. The invention relates to the use of the compounds of the formula I in the treatment and prophylaxis of dysfunctions of the autonomous nervous system, in particular of vagal dysfunctions, for example in the case of cardiovascular diseases, and to their use for preparing medicaments for such treatment and prophylaxis. Furthermore, the invention relates to the use of compounds of the formula I in combination with beta-receptor blockers and to products and pharmaceutical preparations which comprise at least one compound of the formula I and at least one beta-receptor blocker, and to novel compounds.
Compounds of the formula I are known from U.S. Pat. No. 5,574,069 (EP-A-612 724), U.S. Pat. No. 5,776,980, U.S. Pat. No. 5,698,596, and U.S. Pat. No. 5,652,268 (EP-A-727 416), which are incorporated herein by reference and the content of which is part of the present disclosure. In these publications it is described that compounds of the formula I inhibit ATP-sensitive potassium channels in particular at the heart, and that they have direct antiarrhythmic action by influencing the action potential duration of the heart which is a result of the direct effect on the electrical properties of heart muscle cells. Owing to this property, the compounds of the formula I are suitable, for example, for treating ventricular fibrillation and other cardiac arrhythmias. Other pharmacological effects of the compounds of the formula I have hitherto not been described. Surprisingly, it has now been found that the compounds of the formula I also have an effect on the peripheral and/or the central autonomous nervous system. In particular, they influence the vagal nervous system and have a stimulating effect on the vagal nervous system.
In an ideal case, an optimum cooperation, adapted to the particular situation, exists between the sympathetic (=stimulating) nervous system and the vagal (or parasympathetic) (=depressing) nervous system. In the case of a disease, however, this cooperation can be disturbed and a dysfunction of the autonomous nervous system may be present, i.e. an imbalance between the activity of the vagal nervous system and the activity of the sympathetic nervous system. Sympathovagal imbalance is generally understood as an overactivity of the sympathetic (=stimulating) nervous system and/or an impaired function of the vagal (=depressing) nervous system, where the two parts of the nervous system may mutually influence each other. In particular, it is known that an impaired function of the vagal system may result in overactivity of the sympathetic system. To avoid damage to cells or organs of the body by overshooting biological or biochemical processes which are stimulated by excessive activity of the sympathetic nervous system, it is therefore attempted in such cases to balance out a sympathovagal imbalance, for example to reestablish normal vagal activity by treating a vagal dysfunction or impaired function.
Examples of diseases where elimination of a harmful sympathovagal imbalance by treatment of a vagal dysfunction is suitable are organic heart diseases, for example coronary heart disease, cardiac insufficiency and cardiomyopathies. Damage to the health which result from an imbalance of the autonomous nervous system when the dysfunction affects the heart are, for example, weakening of the strength of the heart or sometimes fatal cardiac arrhythmias. The significance of the autonomous nervous system for sudden cardiac death in cases of heart diseases has been described, for example, by P. J. Schwartz (The ATRAMI prospective study: implications for risk stratification after myocardial infarction; Cardiac Electrophysiology Review 1998, 2, 38-40) or T. Kinugawa et al. (Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure; Am. J. Physiol. 1995, 268, R310-316). Experimental investigations with electric stimulation of the vagus of the heart or stimulating analogs of the vagal transmitter acetylcholine, for example carbachol, support the protective effect of vagal activation against fatal cardiac arrhythmias (see, for example, E. Vanoli et al., Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction; Circ. Res. 1991, 68(5), 1471-81).
However, sympathovagal imbalance can also occur, for example, as a consequence of a metabolic disorder, for example diabetes mellitus, (see, for example, A. J. Burger et al., Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus; Am. J. Cardiol. 1997, 80, 1198-1202). Impaired function of the vagal system may also be temporary, for example in cases of oxygen deficit of, for example, the heart, resulting in a reduced secretion of vagal neurotransmitters, for example acetylcholine.
Owing to the surprising capacity of the compounds of the formula I to mend an impaired function of the vagal system, or to reestablish normal vagal activity, these compounds offer an efficient possibility to reduce, to eliminate or to prevent dysfunctions of the autonomous nervous system and their consequences such as, for example, the abovementioned diseases. Thus, a subject of the present invention is the use of benzenesulfonyl(thio)ureas of the formula I
in which
R
1
is hydrogen, methyl or trifluoromethyl;
R
2
is hydrogen, halogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxy-(C
1
-C
4
)-alkoxy-, (C
1
-C
6
)-alkoxy-(C
1
-C
4
)-alkoxy-(C
1
-C
4
)-alkoxy-, (C
1
-C
6
)-alkylthio, (C
1
-C
6
)-fluoroalkoxy or (C
1
-C
6
)-fluoroalkyl;
E is oxygen or sulfur;
Y is a hydrocarbon residue of the formula —(CR
3
2
)
n
— in which the residues R
3
independently of one another are each hydrogen or (C
1
-C
2
)-alkyl and n is 1, 2, 3 or 4;
X is hydrogen, halogen or (C
1
-C
6
)-alkyl;
Z is halogen, nitro, (C
1
-C
4
)-alkoxy or (C
1
-C
4
)-alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios, and/or their physiologically acceptable salts for preparing a medicament for the treatment or prophylaxis of a dysfunction of the autonomous nervous system.
Alkyl is a straight-chain, branched or cyclic saturated hydrocarbon residue. This also applies if the alkyl residue is substituted, such as, for example, in fluoroalkyl residues, or is present as a substituent in another residue, for example in alkoxy residues, alkylthio residues or fluoroalkoxy residues. Examples of straight-chain or branched alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl. Examples of cyclic alkyl residues, which, according to their nature, must have at least three carbon atoms, are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cyclic alkyl residues may additionally carry one or more, for example 1, 2, 3 or 4, (C
1
-C
4
)-alkyl residues or (C
1
-C
4
)-fluoroalkyl residues, for example methyl groups or trifluoromethyl groups.
Examples of the residue alkoxy (=alkyloxy), which is attached via an oxygen atom, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, neopentoxy, isohexoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy. Examples of the residue alkylthio, which is attached via a sulfur atom, are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, neopentylthio, isohexylthio, cyclopropylthio, cyclobutylthio, cyc
Bohn Helmut
Englert Heinrich Christian
Gerlach Uwe
Gögelein Heinz
Heitsch Holger
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Reamer James H.
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