U.S. patent application number 09/986626 was filed with the patent office on 2002-06-27 for 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.
Invention is credited to Bohn, Helmut, Englert, Heinrich Christian, Gerlach, Uwe, Gogelein, Heinz, Heitsch, Holger, Wirth, Klaus.
Application Number | 20020082300 09/986626 |
Document ID | / |
Family ID | 26048790 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082300 |
Kind Code |
A1 |
Wirth, Klaus ; et
al. |
June 27, 2002 |
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
Abstract
Substituted benzenesulfonylureas and -thioureas of the formula I
1 in which R.sup.1, R.sup.2, E, X, Y and Z have the meanings
described herein, 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. The invention also 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.
Inventors: |
Wirth, Klaus; (Kriftel,
DE) ; Englert, Heinrich Christian; (Hofheim, DE)
; Bohn, Helmut; (Schoneck, DE) ; Gogelein,
Heinz; (Frankfurt am Main, DE) ; Heitsch, Holger;
(Mainz-Kastel, DE) ; Gerlach, Uwe; (Hattersheim,
DE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT &
DUNNER LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Family ID: |
26048790 |
Appl. No.: |
09/986626 |
Filed: |
November 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09986626 |
Nov 9, 2001 |
|
|
|
09392747 |
Sep 9, 1999 |
|
|
|
Current U.S.
Class: |
514/584 ;
514/593 |
Current CPC
Class: |
A61P 9/06 20180101; A61K
31/18 20130101; A61P 25/02 20180101; A61P 3/10 20180101; A61P 9/10
20180101; C07C 311/58 20130101; A61P 9/00 20180101; Y10S 514/821
20130101; C08K 5/5406 20130101; A61K 31/64 20130101; C07C 335/42
20130101; A61P 43/00 20180101; A61P 9/04 20180101; A61P 25/00
20180101; C08K 5/5406 20130101; C08L 21/00 20130101 |
Class at
Publication: |
514/584 ;
514/593 |
International
Class: |
A61K 031/18 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 10, 1998 |
DE |
19841534.6 |
Jan 14, 1999 |
DE |
19901061.7 |
Claims
We claim:
1. A method for the treatment or prophylaxis of a disfunction of
the autonomous nervous system, which comprises administering to a
host in need of such treatment or prophylaxis an effective amount
of a benzenesulfonyl(thio)urea of the formula I or a
physiologically acceptable salt thereof, 22in any stereoisomeric
form, or a mixture of benzenesulfonyl(thio)ureas of the formula I
or physiologically acceptable salts thereof, in any stereoisomeric
forms, in which R.sup.1 is hydrogen, methyl or trifluoromethyl;
R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkox-
y-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy or
(C.sub.1-C.sub.6)-fluoroalkyl; E is oxygen or sulfur; Y is a
hydrocarbon residue of the formula --(CR.sup.3.sub.2).sub.n-- in
which the residues R.sup.3 independently of one another are each
hydrogen or (C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4; X is
hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl; Z is halogen, nitro,
(C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.4)-alkyl.
2. A method as claimed in claim 1, wherein in the formula I R.sup.2
is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkox-
y-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-,
(C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy or
(C.sub.1-C.sub.6)-fluoroalkyl; X is halogen or
(C.sub.3-C.sub.6)-alkyl.
3. A method as claimed in claim 1, wherein in the formula I R.sup.1
is hydrogen or methyl; R.sup.2 is hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl- , (C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alk- oxy-,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)--
alkoxy-, (C.sub.1-C.sub.6)-alkylthio,
(C.sub.1-C.sub.6)-fluoroalkoxy or (C.sub.1-C.sub.6)-fluoroalkyl; Y
is a hydrocarbon residue of the formula --(CR.sup.3.sub.2).sub.n--
in which the residues R.sup.3 independently of one another are each
hydrogen or methyl and n is 1, 2, 3 or 4; X is halogen or
(C.sub.3-C.sub.6)-alkyl; Z is (C.sub.1-C.sub.4)-alkoxy.
4. A method as claimed in claim 1, wherein in the formula I R.sup.1
is hydrogen or methyl; R.sup.2 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alko- xy- or
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-
-alkoxy-; Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- in which the residues R.sup.3
independently of one another are each hydrogen or methyl and n is
1, 2, 3 or 4; X is halogen or (C.sub.3-C.sub.6)-alkyl; Z is
(C.sub.1-C.sub.4)-alkoxy.
5. A method as claimed in claim 1, wherein in the formula I R.sup.1
is hydrogen or methyl; R.sup.2 is methyl, methoxy or
2-methoxyethoxy-; Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- in which the residues R.sup.3
independently of one another are each hydrogen or methyl and n is 2
or 3; X is halogen or (C.sub.3-C.sub.6)-alkyl; Z is
(C.sub.1-C.sub.4)-alkoxy.
6. A method as claimed in claim 1, wherein in the formula I R.sup.1
is methyl; R.sup.2 is methyl, methoxy or 2-methoxyethoxy-; E is
sulfur; Y is a hydrocarbon residue of the formula
--(CH.sub.2).sub.n-- in which n is 2 or 3; X is halogen or
(C.sub.3-C.sub.6)-alkyl; Z is (C.sub.1-C.sub.4)-alkoxy.
7. A method as claimed in claim 1, which comprises administering
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3--
methylthiourea,
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-(2-methoxye-
thoxy)phenyl]sulfonyl]-3-methylthiourea, or
1-[[5-[2-(5-tert-butyl-2-metho-
xybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, or a
physiologically acceptable salt of
1-[[5-[2-(5-chloro-2-methoxybenzamido)-
ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea,
1-[[5-[2-(5-chloro-2-me-
thoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthiourea-
, or
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulf-
onyl]-3-methylthiourea.
8. A method as claimed in claim 1, which comprises administering a
sodium salt of a benzenesulfonyl(thio)urea of the formula I.
9. A method as claimed in claim 1, wherein the disfunction of the
autonomous nervous system is a vagal disfunction.
10. A method as claimed in claim 1, wherein the disfunction of the
autonomous nervous system is a vagal disfunction of the heart.
11. A method as claimed in claim 1, wherein the disfunction of the
autonomous nervous system is a vagal disfunction of the heart in
the case of coronary heart disease, angina pectoris, cardiac
infarction, postmyocardial infarction, cardiac insufficiency,
cardiomyopathy or diabetes mellitus.
12. A method as claimed in claim 1, which further comprises the
simultaneous, separate or sequential administration to the host of
at least one beta-receptor blocker or a physiologically acceptable
salt thereof.
13. A method as claimed in claim 12, which comprises administering
the beta-receptor blocker alprenolol, oxprenolol, penbutolol,
bupranolol, metoprolol, betaxolol, atenolol, acebutolol,
metipranolol, propranolol, nadolol, pindolol, mepindolol,
carteolol, timolol, sotalol, carvedilol, bisoprolol, celiprolol,
carazolol, talinolol, tertatolol, or bopindolol, or a
physiologically acceptable salt of alprenolol, oxprenolol,
penbutolol, bupranolol, metoprolol, betaxolol, atenolol,
acebutolol, metipranolol, propranolol, nadolol, pindolol,
mepindolol, carteolol, timolol, sotalol, carvedilol, bisoprolol,
celiprolol, carazolol, talinolol, tertatolol, or bopindolol.
14. A kit for the treatment or prophylaxis of a disfunction of the
autonomous nervous system, which comprises a
benzenesulfonyl(thio)urea of the formula I or a physiologically
acceptable salt thereof, 23in any stereoisomeric form, or a mixture
of benzenesulfonyl(thio)ureas of the formula I or physiologically
acceptable salts thereof, in any stereoisomeric forms, in which
R.sup.1 is hydrogen, methyl or trifluoromethyl; R.sup.2 is
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl; E is oxygen or sulfur; Y is a
hydrocarbon residue of the formula --(CR.sup.3.sub.2).sub.n-- in
which the residues R.sup.3 independently of one another are each
hydrogen or (C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4; X is
hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl; Z is halogen, nitro,
(C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.4)-alkyl; and a
beta-receptor blocker or physiologically acceptable salt thereof,
for simultaneous, separate or sequential administration with the
benzenesulfonyl(thio)urea of the formula I, physiologically
acceptable salt of the benzenesulfonyl(thio)urea of the formula I,
or mixture thereof.
15. A pharmaceutical preparation, comprising a
benzenesulfonyl(thio)urea of the formula I or a physiologically
acceptable salt thereof, 24in any stereoisomeric form, or a mixture
of benzenesulfonyl(thio)ureas of the formula I or physiologically
acceptable salts thereof, in any stereoisomeric forms, in which
R.sup.1 is hydrogen, methyl or trifluoromethyl; R.sup.2 is
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl; E is oxygen or sulfur; Y is a
hydrocarbon residue of the formula --(CR.sup.3.sub.2).sub.n-- in
which the residues R.sup.3 independently of one another are each
hydrogen or (C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4; X is
hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl; Z is halogen, nitro,
(C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.4)-alkyl; and at least
one beta-receptor blocker or physiologically acceptable salt
thereof; and a physiologically acceptable carrier.
16. A pharmaceutical preparation as claimed in claim 15, which
comprises
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3--
methylthiourea,
1-[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-(2-methoxyet-
hoxy)phenyl]sulfonyl]-3-methylthiourea, or
1-[[5-[2-(5-tert-butyl-2-methox-
ybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, or a
physiologically acceptable salt of
1-[[5-[2-(5-chloro-2-methoxybenzamido)-
ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea,
1-[[5-[2-(5-chloro-2-me-
thoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthiourea-
, or
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulf-
onyl]-3-methylthiourea.
17. A pharmaceutical preparation as claimed in claim 15, which
comprises at least one sodium salt of the compound of the formula
I.
18. A pharmaceutical preparation as claimed in claim 15, which
comprises the beta-receptor blocker alprenolol, oxprenolol,
penbutolol, bupranolol, metoprolol, betaxolol, atenolol,
acebutolol, metipranolol, propranolol, nadolol, pindolol,
mepindolol, carteolol, timolol, sotalol, carvedilol, bisoprolol,
celiprolol, carazolol, talinolol, tertatolol, or bopindolol, or a
physiologically acceptable salt of alprenolol, oxprenolol,
penbutolol, bupranolol, metoprolol, betaxolol, atenolol,
acebutolol, metipranolol, propranolol, nadolol, pindolol,
mepindolol, carteolol, timolol, sotalol, carvedilol, bisoprolol,
celiprolol, carazolol, talinolol, tertatolol, or bopindolol.
19.
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfo-
nyl]-3-methylthiourea or a physiologically acceptable salt
thereof.
20.
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfo-
nyl]-3-methylurea or a physiologically acceptable salt thereof.
21.
1-[[5-[2-(5-Isopropyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfon-
yl]-3-methylthiourea or a physiologically acceptable salt
thereof.
22.
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)ph-
enyl]sulfonyl]-3-methylthiourea or a physiologically acceptable
salt thereof.
23.
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfo-
nyl]-3-methylthiourea sodium salt.
24. A pharmaceutical preparation, comprising a compound of claim 19
and a physiologically acceptable carrier.
25. A pharmaceutical preparation, comprising a compound of claim 20
and a physiologically acceptable carrier.
26. A pharmaceutical preparation, comprising a compound of claim 21
and a physiologically acceptable carrier.
27. A pharmaceutical preparation, comprising a compound of claim 22
and a physiologically acceptable carrier.
28. A pharmaceutical preparation, comprising the compound of claim
23 and a physiologically acceptable carrier.
29. A pharmaceutical preparation for the treatment or prophylaxis
of a disfunction of the autonomous nervous system, comprising a
benzenesulfonyl(thio)urea of the formula I or a physiologically
acceptable salt thereof, 25in any stereoisomeric form, or a mixture
of benzenesulfonyl(thio)ureas of the formula I or physiologically
acceptable salts thereof, in any stereoisomeric forms, in which
R.sup.1 is hydrogen, methyl or trifluoromethyl; R.sup.2 is
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkox-
y-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy or
(C.sub.1-C.sub.6)-fluoroalkyl; E is oxygen or sulfur; Y is a
hydrocarbon residue of the formula --(CR.sup.3.sub.2).sub.n-- in
which the residues R.sup.3 independently of one another are each
hydrogen or (C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4; X is
hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl; Z is halogen, nitro,
(C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.4)-alkyl; and a
physiologically acceptable carrier.
30. A kit as claimed in claim 14, which comprises
1-[[5-[2-(5-chloro-2-met-
hoxy-benzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea,
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]su-
lfonyl]-3-methylthiourea, or
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)eth-
yl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, or a
physiologically acceptable salt of
1-[[5-[2-(5-chloro-2-methoxy-benzamido)ethyl]-2-methox-
yphenyl]sulfonyl]-3-methylthiourea,
1-[[5-[2-(5-chloro-2-methoxybenzamido)-
ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthiourea, or
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl-]sulfony-
l]-3-methylthiourea.
31. A kit as claimed in claim 14, which comprises at least one
sodium salt of the compound of the formula I.
32. A kit as claimed in claim 14, which comprises the beta-receptor
blocker alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol,
betaxolol, atenolol, acebutolol, metipranolol, propranolol,
nadolol, pindolol, mepindolol, carteolol, timolol, sotalol,
carvedilol, bisoprolol, celiprolol, carazolol, talinolol,
tertatolol, or bopindolol, or a physiologically acceptable salt of
alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol,
betaxolol, atenolol, acebutolol, metipranolol, propranolol,
nadolol, pindolol, mepindolol, carteolol, timolol, sotalol,
carvedilol, bisoprolol, celiprolol, carazolol, talinolol,
tertatolol, or bopindolol.
Description
[0001] 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.
[0002] Substituted benzenesulfonylureas and -thioureas of the
formula I 2
[0003] in which R.sup.1, R.sup.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.
[0004] 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.
[0005] 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.
[0006] 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,
37, 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).
[0007] 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.
[0008] 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 3
[0009] in which
[0010] R.sup.1 is hydrogen, methyl or trifluoromethyl;
[0011] R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl;
[0012] E is oxygen or sulfur;
[0013] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or
(C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4;
[0014] X is hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl;
[0015] Z is halogen, nitro, (C.sub.1-C.sub.4)-alkoxy or
(C.sub.1-C.sub.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.
[0016] 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.sub.1-C.sub.4)-alkyl residues or (C.sub.1-C.sub.4)-fluoroalkyl
residues, for example methyl groups or trifluoromethyl groups.
[0017] 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, cyclopentylthio or cyclohexylthio.
[0018] Fluoroalkyl is an alkyl residue in which one or more
hydrogen atoms of an alkyl residue which is as defined above are
replaced by fluorine atoms. A fluoroalkyl residue may contain one
or more fluorine atoms, for example 1, 2, 3, 4, 5, 6 or 7. At most,
all hydrogen atoms may have been exchanged, i.e.
perfluorosubstitution is present. Examples of fluoroalkyl are
trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.
Fluoroalkoxy is an alkoxy residue as defined above in which, as
illustrated above, one or more hydrogen atoms are replaced by
fluorine atoms.
[0019] For all alkyl groups in the residues alkoxy-alkoxy- and
alkoxy-alkoxy-alkoxy-, which are attached via an oxygen atom, the
above definitions and illustrations apply independently of one
another. In the divalent alkyl groups contained in these groups,
the two free bonds via which these groups are attached to the
neighboring groups, can be in any positions, for example in the
1,1-position of an alkyl residue, in the 1,2-position, in the
1,3-position or 1,4-position. Examples of such divalent residues
are methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene,
1,4-butylene or 2,2-dimethyl-1,3-propylene. A preferred divalent
residue of this type is 1,2-ethylene. Examples of alkoxy-alkoxy-
residues are methoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy,
4-methoxybutoxy, 6-methoxyhexoxy, 2-ethoxyethoxy,
2-ethoxy-2-methylethoxy- , 3-ethoxypropoxy, 2-isobutoxyethoxy,
2-tert-butoxyethoxy, 2-cyclopropoxyethoxy, 2-cyclopentoxyethoxy.
Examples of alkoxy-alkoxy-alkoxy-residues are
(2-methoxyethoxy)methoxy, 2-(2-methoxyethoxy)ethoxy,
2-(2-isopropoxyethoxy)ethoxy, 2-(2-n-butoxyethoxy)ethoxy,
2-(2-cyclopropoxyethoxy)ethoxy, 3-(2-methoxyethoxy)propoxy,
2-(2-methoxy-2-methylethoxy)-2-methylethoxy.
[0020] Examples of halogen are fluorine, chlorine, bromine and
iodine, in particular fluorine and chlorine.
[0021] The present invention embraces all stereoisomeric forms of
the compounds of the formula 1. Asymmetric centers contained in the
compounds of the formula 1, for example in the group Y, can each,
independently of one another, have the S configuration or the R
configuration. The invention includes all possible enantiomers and
diastereomers, and also mixtures of two or more stereoisomeric
forms, for example mixtures of enantiomers and/or diastereomers, in
all ratios. The invention provides the enantiomers therefore in
enantiomerically pure form, both as levorotatory and as
dextrorotatory antipodes, in the form of racemates and in the form
of mixtures of the two enantiomers in all ratios. The invention
provides diastereomers both in pure form and in the form of
mixtures of two or more diastereomers in all quantity ratios. Meso
compounds, for example, are also included. If a cis/trans isomerism
is present, the invention provides both the cis form and the trans
form and mixtures of these forms in all ratios. The individual
stereoisomers can be prepared, if desired, by separating a mixture
according to customary methods, for example by chromatography or
crystallization, or by using stereochemically uniform starting
materials in the synthesis. If appropriate, derivatization may be
carried out prior to a separation of stereoisomers. A mixture of
stereoisomers can be separated at the stage of the compounds of the
formula I or at the stage of an intermediate in the course of the
synthesis. The invention also includes all tautomeric forms of the
compounds of the formula I.
[0022] Physiologically acceptable salts of the compounds of the
formula I are in particular pharmaceutically utilizable salts or
non-toxic salts. They may contain inorganic or organic salt
components (see also Remington's Pharmaceutical Sciences (A. R.
Gennaro (Editor), Mack Publishing Co., Easton Pa., 17.sup.th
edition, page 1418 (1985)). Such salts can be prepared, for
example, from compounds of the formula I with suitable inorganic or
organic bases, for example with alkali metal or alkaline earth
metal compounds, such as sodium hydroxide or potassium hydroxide,
or with ammonia or organic amino compounds or ammonium hydroxides.
Reactions of compounds of the formula I with bases for preparing
the salts are generally carried out in accordance with customary
procedures in a solvent or diluent. Salts which are advantageous
owing to their physiological and chemical stability are in many
cases sodium, potassium, magnesium or calcium salts or ammonium
salts, in particular sodium salts. Salt formation at the nitrogen
atom of the (thio)urea group which is attached to the sulfonyl
group leads to compounds of the formula II 4
[0023] in which R.sup.1, R.sup.2, E, X, Y and Z have the meanings
given above and the cation M is, for example, an alkali metal ion
or an equivalent of an alkaline earth metal ion, for example the
sodium, potassium, magnesium or calcium ion, or is the
unsubstituted ammonium ion or an ammonium ion having one or more
organic residues. An ammonium ion representing M can, for example,
also be the cation obtained by protonation from an amino acid, in
particular a basic amino acid, such as, for example, lysine or
arginine.
[0024] The present invention also includes all solvates of
compounds of the formula I and their physiologically acceptable
salts, for example hydrates or adducts with alcohols, and also
derivatives of compounds of the formula I and prodrugs and active
metabolites.
[0025] In the formula I R.sup.1 is preferably hydrogen or methyl,
particularly preferably methyl.
[0026] If R.sup.2 in the formula I is halogen, the residue is
preferably chlorine or fluorine. If R.sup.2 in the formula I is
(C.sub.1-C.sub.6)-alkyl, the residue is preferably
(C.sub.1-C.sub.4)-alkyl, in particular methyl. If R.sup.2 in the
formula I is (C.sub.1-C.sub.6)-alkoxy, the residue is preferably
(C.sub.1-C.sub.4)-alkoxy, in particular methoxy. If R.sup.2 in the
formula I is (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-,
the residue is preferably
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-, in particular
2-((C.sub.1-C.sub.4)-alkoxy)ethoxy-, specifically 2-methoxyethoxy-.
If R.sup.2 in the formula I is (C.sub.1-C.sub.6)-alkoxy-
-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-, the residue is
preferably
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.s-
ub.4)-alkoxy-, in particular
2-(2-((C.sub.1-C.sub.4)-alkoxy)ethoxy)ethoxy-- , specifically
2-(2-methoxyethoxy)ethoxy-. A group of preferred residues R.sup.2
is formed by the residues (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy and
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-a- lkoxy-, in particular
the residues (C.sub.1-C.sub.6)-alkoxy and
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-, specifically
the residues methoxy and 2-methoxyethoxy-.
[0027] The residues R.sup.3 independently of one another are
preferably hydrogen or methyl, particularly preferably hydrogen. n
is preferably 2 or 3. The group Y preferably contains up to four
carbon atoms. Particularly preferably, Y is the group
--(CH.sub.2).sub.n--, where n is 2 or 3, or the group
--CHR.sup.3--CH.sub.2-- in which R.sup.3 is methyl or ethyl and the
group --CHR.sup.3-- is attached to the NH group. Very particularly
preferably, Y is the group --CH.sub.2--CH.sub.2--.
[0028] X is preferably halogen or (C.sub.3-C.sub.6)-alkyl, for
example fluorine, chlorine, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, tert-amyl or 1,1-dimethylpropyl, in
particular chlorine or tert-butyl. Z is preferably halogen, nitro,
(C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.4)-alkyl, particularly
preferably (C.sub.1-C.sub.4)-alkoxy- , for example methoxy. The
residues X and Z can be in any position of the phenyl residue to
which they are attached. Preferably, X is attached in the
5-position and Z in the 2-position of the phenyl residue, in each
case relative to the group C(.dbd.O)--NH in the 1-position.
[0029] If in the compounds of the formula I according to the
invention the group E is oxygen, ureas of the formula la are
present. If E is sulfur, thioureas of the formula Ib are present. E
is preferably sulfur. 5 6
[0030] Preferred compounds of the formula I for the use according
to the invention are compounds in which one or more of the residues
have preferred meanings, all combinations of preferred meanings
being a subject of the present invention.
[0031] For example, preference is given to the use of compounds of
the formula I in which
[0032] R.sup.1 is hydrogen, methyl or trifluoromethyl;
[0033] R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl;
[0034] E is oxygen or sulfur;
[0035] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or
(C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4;
[0036] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0037] Z is halogen, nitro, (C.sub.1-C.sub.4)-alkoxy or
(C.sub.1-C.sub.4)-alkyl;
[0038] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0039] Particular preference is given to the use of compounds of
the formula I in which
[0040] R.sup.1 is hydrogen or methyl;
[0041] R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl;
[0042] E is oxygen or sulfur;
[0043] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or methyl and n is
1, 2, 3 or 4;
[0044] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0045] Z is (C.sub.1-C.sub.4)-alkoxy;
[0046] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0047] More particular preference is given to the use of compounds
of the formula I in which
[0048] R.sup.1 is hydrogen or methyl;
[0049] R.sup.2 is hydrogen or halogen;
[0050] E is oxygen or sulfur;
[0051] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or methyl and n is
1, 2, 3 or 4;
[0052] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0053] Z is (C.sub.1-C.sub.4)-alkoxy;
[0054] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0055] More particular preference is also given to the use of
compounds of the formula I in which
[0056] R.sup.1 is hydrogen or methyl;
[0057] R.sup.2 is (C.sub.1-C.sub.6)-alkylthio,
(C.sub.1-C.sub.6)-fluoroalk- oxy or
(C.sub.1-C.sub.6)-fluoroalkyl;
[0058] E is oxygen or sulfur;
[0059] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or methyl and n is
1, 2, 3 or 4;
[0060] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0061] Z is (C.sub.1-C.sub.4)-alkoxy;
[0062] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0063] More particular preference is furthermore also given to the
use of compounds of the formula I in which
[0064] R.sup.1 is hydrogen or methyl;
[0065] R.sup.2 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy- or
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkox-
y-;
[0066] E is oxygen or sulfur;
[0067] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3.
independently of one another are each hydrogen or methyl and n is
1, 2, 3 or 4;
[0068] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0069] Z is (C.sub.1-C.sub.4)-alkoxy;
[0070] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0071] Very particular preference is given to the use of compounds
of the formula I in which R.sup.1 is hydrogen or methyl;
[0072] R.sup.2 is methyl, methoxy or 2-methoxyethoxy-;
[0073] E is oxygen or sulfur;
[0074] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3.
independently of one another are each hydrogen or methyl and n is 2
or 3;
[0075] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0076] Z is (C.sub.1-C.sub.4)-alkoxy;
[0077] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0078] Specific preference is given to the use of compounds of the
formula I in which
[0079] R.sup.1 is methyl;
[0080] R.sup.2 is methyl, methoxy or 2-methoxyethoxy;
[0081] E is sulfur;
[0082] Y is a hydrocarbon residue of the formula
--(CH.sub.2).sub.n-- in which n is 2 or 3;
[0083] X is halogen or (C.sub.3-C.sub.6)-alkyl;
[0084] Z is (C.sub.1-C.sub.4)-alkoxy;
[0085] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts.
[0086] The compounds of the formula I according to the invention
can be prepared, for example, by the processes below.
[0087] (a) Aromatic sulfonamides of the formula III or their salts
of the formula IV can be reacted with R.sup.1-substituted
isocyanates of the formula V to give substituted
benzenesulfonylureas of the formula Ia 7
[0088] Suitable cations M.sup.1 in the salts of the formula IV are
alkali metal ions or alkaline earth metal ions such as, for
example, sodium ions or potassium ions, or ammonium ions such as,
for example, tetraalkylammonium ions. Equivalent to the
R.sup.1-substituted isocyanates of the formula V, it is possible to
use R.sup.1-substituted carbamic acid esters, R.sup.1-substituted
carbamoyl halides or R.sup.1-substituted ureas.
[0089] (b) Benzenesulfonylureas of the formula Ia which are
unsubstituted at the urea group and in which R.sup.1 is hydrogen,
can be prepared by reacting aromatic benzenesulfonamides of the
formula III or their salts of the formula IV with trialkylsilyl
isocyanates, such as trimethylsilyl isocyanate, or with silicon
tetraisocyanate and hydrolysis of the silicon-substituted
benzenesulfonylureas which are primarily formed.
[0090] Furthermore, compounds of the formula Ia in which R.sup.1 is
hydrogen can be obtained from benzenesulfonamides of the formula
III or their salts of the formula IV by reaction with halogen
cyanides and hydrolysis of the N-cyanosulfonamides which are
primarily formed with mineral acids at temperatures between
0.degree. C. and 100.degree. C.
[0091] (c) Benzenesulfonylureas of the formula Ia can be prepared
from aromatic benzenesulfonamides of the formula III or their salts
of the formula IV using R.sup.1-substituted trichloroacetamides of
the formula VI in the presence of a base in an inert solvent
according to Synthesis 1987, 734-735, at temperatures between
25.degree. C. and 150.degree. C.
Cl.sub.3C--CO--NH--R.sup.1 VI
[0092] Suitable bases are, for example, alkali metal or alkaline
earth metal hydroxides, hydrides, amides or alkoxides, such as
sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium
hydride, potassium hydride, calcium hydride, sodium amide,
potassium amide, sodium methoxide, sodium ethoxide, potassium
methoxide or potassium ethoxide. Suitable inert solvents are
ethers, such as tetrahydrofuran, dioxane or ethylene glycol
dimethyl ether (DME), ketones, such as acetone or butanone,
nitrites, such as acetonitrile, nitro compounds, such as
nitromethane, esters, such as ethyl acetate, amides, such as
dimethylformamide (DMF) or N-methylpyrrolidone (NMP),
hexamethylphosphoric triamide, sulfoxides, such as dimethyl
sulfoxide (DMSO), sulfones, such as sulfolane, hydrocarbons, such
as benzene, toluene, xylenes. Moreover, mixtures of these solvents
with one another are also suitable.
[0093] (d) Benzenesulfonylthioureas of the formula Ib can be
prepared from benzenesulfonamides of the formula III or their salts
of the formula IV and R.sup.1-substituted isothiocyanates of the
formula VII.
R.sup.1--N.dbd.C.dbd.S VII
[0094] Benzenesulfonylthioureas of the formula Ib which are
unsubstituted at the thiourea group and in which R.sup.1 is
hydrogen, can be prepared by reacting aromatic benzenesulfonamides
of the formula III or their salts of the formula IV with
trialkylsilyl isothiocyanates, such as trimethylsilyl
isothiocyanate, or with silicon tetraisothiocyanate and hydrolysis
of the silicon-substituted benzenesulfonylthioureas which are
primarily formed. Furthermore, it is possible to prepare compounds
of the formula Ib in which R.sup.1 is hydrogen by reacting aromatic
benzenesulfonamides of the formula III or their salts of the
formula IV with benzoyl isothiocyanate and subsequently reacting
the benzoyl-substituted benzenesulfonylthiourea intermediates with
aqueous mineral acids. Similar processes are described in J. Med.
Chem. 1992, 35, 1137-1144.
[0095] (e) Substituted benzenesulfonylureas of the formula Ia can
be prepared by conversion reactions from benzenesulfonylthioureas
of the formula Ib. Desulfurization, i.e. replacement of the sulfur
atom in the corresponding benzenesulfonylthiourea by an oxygen
atom, can be carried out, for example, with the aid of oxides or
salts of heavy metals or by using oxidizing agents, such as
hydrogen peroxide, sodium peroxide or nitrous acid. Thioureas can
also be desulfurized by treatment with phosgene or phosphorus
pentachloride. Chloroformic acid amidines or carbodiimides are
obtained as intermediate compounds and can be converted into the
corresponding substituted benzenesulfonylureas, for example, by
hydrolysis or by adding on water.
[0096] (f) Benzenesulfonylureas of the formula Ia can be prepared
from benzenesulfonyl halides of the formula VIII using
R.sup.1-substituted ureas or R.sup.1-substituted
bis(trialkylsilyl)ureas. The trialkylsilyl protective group can be
removed from the resulting (trialkylsilyl)benzenesulfonylurea
according to standard methods. Furthermore, the sulfonyl chlorides
of the formula VIII can be reacted with parabanic acid to give
benzenesulfonyl parabanic acids the hydrolysis of which, with
mineral acids, affords the corresponding benzenesulfonylureas of
the formula Ia. 8
[0097] (g) Benzenesulfonylureas of the formula Ia can be prepared
by reacting amines of the formula R.sup.1--NH.sub.2 with
benzenesulfonyl isocyanates of the formula IX. Likewise, amines of
the formula R.sup.1--NH.sub.2 can be reacted with
benzenesulfonylcarbamic acid esters, with -carbamoyl halides or
with benzenesulfonylureas of the formula Ia in which R.sup.1 is
hydrogen to give compounds of the formula Ia. 9
[0098] (h) Benzenesulfonylthioureas of the formula Ib can be
prepared by reacting amines of the formula R.sup.1--NH.sub.2 with
benzenesulfonyl isothiocyanates of the formula X. Likewise, amines
of the formula R.sup.1--NH.sub.2 can be reacted with
benzenesulfonylcarbamic acid thioesters or -carbamoyl thiohalides
to give compounds of the formula Ib. 10
[0099] (i) Appropriately substituted benzenesulfenyl- or
-sulfinylureas can be oxidized with oxidizing agents such as
hydrogen peroxide, sodium peroxide or nitrous acid to give
benzenesulfonylureas of the formula Ia.
[0100] The starting materials for the abovementioned synthesis
processes of the compounds of the formula I can be prepared by
methods known per se, such as are described in the literature (for
example in the standard works such as Houben-Weyl, Methoden der
Organischen Chemie [Methods of Organic Chemistry], Georg Thieme
Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc.,
New York; or in the abovementioned patent references), and under
reaction conditions which are known and suitable for the reactions
mentioned. Variants which are known per se but which are not
mentioned in more detail here can also be utilized for these
reactions. If desired, the starting materials can also be formed in
situ, so that they are not isolated from the reaction mixture but
are further reacted immediately.
[0101] Thus, appropriately substituted amines of the formula XI can
be acylated and subjected to halosulfonation. In the formula XI,
R.sup.2 and Y have the meanings given above. Suitable acylating
agents for acylating the amino group in the compounds of 11
[0102] the formula XI are advantageously the alkyl esters, halides
(for example chlorides or bromides) or anhydrides of carboxylic
acids of the formula R.sup.4--COB. R.sup.4 is here, for example, a
trihalomethyl residue, a (C.sub.1-C.sub.4)-alkyl residue or a
phenyl residue. If R.sup.4 is a phenyl residue, the compound of the
formula R.sup.4-COB is a benzoic acid derivative. The benzoic acid
derivative can be unsubstituted or substituted by one or two
identical or different residues X and Z. Here X and Z are as
defined above, i.e. X can be hydrogen, (C.sub.1-C.sub.6)-alkyl or
halogen and Z can be halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy or nitro. The group B is a leaving group
such as, for example, halogen, (C.sub.1-C.sub.4)-alkox- y,
trihaloacetoxy or (C.sub.1-C.sub.4)-alkylcarbonyloxy. Examples of
compounds of the formula R.sup.4-COB are acetic anhydride,
trihaloacetic anhydride, acetyl halides, trihaloacetyl halides,
propionyl chloride, isobutyryl bromide and isobutyryl chloride,
formic acid/acetic anhydride, benzoyl chloride and substituted
benzoic acid derivatives, such as 5-chloro-2-methoxybenzoyl
chloride or 5-chloro-2-methoxybenzoic anhydride or
(C.sub.1-C.sub.4)-alkyl 5-chloro-2-methoxybenzoate,
5-tert-butyl-2-methoxybenzoyl chloride or 2,5-difluorobenzoyl
chloride. The syntheses of the compounds of the formula XII are
preferably carried out with addition of a tertiary amine base, such
as, for example, pyridine or a trialkylamine, in the presence or
absence of an inert solvent, the presence of a catalyst such as,
for example, dimethylaminopyridine also being possible. The
reaction is generally carried out at temperatures between
approximately 0.degree. C. and 160.degree. C., preferably between
20.degree. C. and 150.degree. C. The acyl group in the compounds of
the formula XII can be a protective group or, in the case of the
benzoic acid derivatives, also part of the compounds of the formula
I. Suitable inert solvents for the acylation are, for example,
ethers, such as tetrahydrofuran, dioxane or glycol ethers, such as
ethylene glycol monomethyl ether or ethylene glycol monoethyl ether
(methylglycol or ethylglycol) or ethylene glycol dimethyl ether,
ketones, such as acetone or butanone, nitriles, such as
acetonitrile, nitro compounds, such as nitromethane, esters, such
as ethyl acetate, amides, such as DMF or NMP, hexamethylphosphoric
triamide, sulfoxides, such as DMSO, chlorinated hydrocarbons, such
as dichloromethane, chloroform, trichloroethylene,
1,2-dichloroethane or carbon tetrachloride, or hydrocarbons, such
as benzene, toluene or xylenes. Furthermore suitable are mixtures
of these solvents with one another.
[0103] From the compounds of the formula XII, the sulfonamides of
the formula XII can be prepared according to methods known per se,
under reaction conditions which are 12
[0104] suitable and known for such reactions. Variants which are
known per se but which are not mentioned in more detail here also
can be utilized for these reactions. If desired, the syntheses can
be carried out in one, two or several steps. Particular preference
is given to processes in which the acylated amine of the formula
XII is converted by electrophilic reagents in the presence or
absence of inert solvents at temperatures between -10.degree. C.
and 120.degree. C., preferably between 0.degree. C. and 100.degree.
C., into aromatic sulfonic acids or their derivatives, such as, for
example, sulfonyl halides. It is possible to carry out, for
example, sulfonations using sulfuric acids or oleum,
halosulfonations using halosulfonic acids, reactions with sulfuryl
halides in the presence of anhydrous metal halides, or reactions
with thionyl halides in the presence of anhydrous metal halides
with subsequent oxidation, carried out in a manner known per se, to
give aromatic sulfonyl chlorides. If the primary reaction products
are sulfonic acids these can be converted into the sulfonyl halides
either directly or by treatment with tertiary amines such as, for
example, pyridine or trialkylamines or with alkali metal or
alkaline earth metal hydroxides or reagents which form these basic
compounds in situ, in a known manner using acid halides such as,
for example, phosphorus trihalides, phosphorus pentahalides,
phosphorus oxichlorides, thionyl halides or oxalyl halides. The
conversion of the sulfonic acid derivatives into sulfonamides can
be carried out in a manner known from the literature. Preference is
given to reacting the sulfonyl chlorides in inert solvents at
temperatures between 0.degree. C. and 100.degree. C. with aqueous
ammonia in the absence or presence of an organic solvent.
Furthermore, aromatic sulfonamides can be synthesized according to
the processes described in the literature from the acylated amines
of the formula XII by reaction with organo(alkali or alkaline
earth) metallic reagents in inert solvents and under an atmosphere
of inert gas at temperatures from -100.degree. C. to 50.degree. C.,
preferably from -100.degree. C. to 30.degree. C., and with sulfur
dioxide and subsequent thermal treatment with amidosulfonic
acid.
[0105] If the acyl group in the compound of the formula XIII acts
as a protective group for the amino group, this protective group
can be removed by treatment with acids or bases after the
introduction of the sulfonamide group. Cleavage with aqueous acids
or with acids in inert solvents may afford the acid addition salt
of the amino compound. Suitable for this protective group removal
are, for example, sulfuric acid, hydrohalic acids, such as
hydrochloric acid or hydrobromic acid, phosphoric acids, such as
orthophosphoric acid, or organic acids. The removal of the amino
protective group in the compound of the formula XIII with bases can
be carried out in aqueous or inert solvents. Suitable bases are,
for example, alkali metal or alkaline earth metal hydroxides, such
as sodium hydroxide, potassium hydroxide or calcium hydroxide, or
alkali metal or alkaline earth metal alkoxides, such as sodium
methoxide, sodium ethoxide, potassium methoxide or potassium
ethoxide. From the sulfonamide-substituted amines or their acid
addition compounds prepared in this manner, it is possible to
prepare the benzenesulfonamides of the formula III by acylation
with substituted benzoic acids or benzoic acid derivatives, as
illustrated above for the acylation of the compounds of the formula
XI.
[0106] The compounds of the formula I can have one or more chiral
centers. Consequently, they can be obtained in their preparation as
racemate or else, if optically active starting materials are used,
in optically active form. If the compounds have two or more chiral
centers, they can be obtained in the synthesis as mixtures of
racemates from which the individual isomers can be isolated in pure
form, for example by recrystallization from inert solvents. If
desired, the racemates obtained can be separated by methods known
per se, mechanically or chemically, into their enantiomers. Thus,
diastereomers can be formed from the racemate by reaction with an
optically active resolving agent. Suitable resolving agents for
basic compounds are, for example, optically active acids, such as
the R- or R,R- and S- or S,S-forms of tartaric acid,
dibenzoyltartaric acid, diacetyltartaric acid, camphorsulfonic
acids, mandelic acids, malic acid or lactic acid. For separation,
it is furthermore possible to acylate carbinols with the aid of
chiral acylating agents, for example R- or S-.alpha.-methylbenzyl
isocyanate, followed by separation. The different forms of the
diastereomers can be separated in a manner known per se, for
example by fractional crystallization, and the enantiomers can be
liberated from the diastereomers in a manner known per se.
Separation of enantiomers is furthermore possible by chromatography
over optically active stationary phases.
[0107] Depending on the nature of the residues R.sup.1, R.sup.2,
R.sup.3, E, X, Y and Z, in individual cases one or other of the
abovementioned processes for the preparation of the compounds of
the formula I will be unsuitable, or at least require measures for
the protection of active groups. Such cases, which are relatively
rare, will easily be recognized by the person skilled in the art,
and it does not cause any difficulties to employ another of the
described synthetic routes successfully in such cases. With respect
to the preparation of the compounds of the formula I to be used
according to the invention, 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) are expressly incorporated herein by way
of reference.
[0108] Owing to their ability to reduce or eliminate insufficient
function of the vagal nervous system and thus vagal dysfunctions
and/or a dysfunction of the autonomous nervous system, the
compounds of the formula I are useful agents for the treatment and
prophylaxis of diseases which are associated with such impaired
functions or dysfunctions of the vagal nervous system or which are
caused by them, or for the treatment or prophylaxis of which an
increase or normalization of the activity of the vagal nervous
system is aimed for. The effect of the compounds of the formula I
on the vagal nervous system can be demonstrated, for example, in
the pharmacological mouse model described below. The effect can
also be demonstrated, for example, in rats, guinea pigs, rabbits,
dogs, monkeys or pigs.
[0109] Diseases and pathological conditions where the treatment or
prophylaxis of an impaired function of the vagal nervous system or
a dysfunction of the autonomous nervous system is indicated have
already been mentioned above. Besides being generally suitable for
the treatment or prophylaxis of a dysfunction of the autonomous
nervous system and in particular a vagal dysfunction, the compounds
of the formula I and their physiologically acceptable salts are
specifically suitable for use in disorders of the cardiovascular
system and in heart diseases for the treatment or prophylaxis of a
sympathovagal imbalance or for the treatment and prophylaxis of a
vagal dysfunction of the heart. Examples of heart diseases and
conditions of this kind are coronary heart disease, angina
pectoris, cardiac infarction, postmyocardial infarction, cardiac
insufficiency, cardiomyopathies, heart transplants, or vagal
dysfunctions of the heart in cases of diabetes mellitus. Since the
compounds of the formula I have, besides their known direct effect
on the heart, i.e. besides the effect on the action potential of
the heart muscle cells, also an indirect effect on the nervous
system of the heart or on the parts of the nervous system which act
on the heart, they can reduce or prevent undesirable consequences
for the heart which are, in the state of disease in question,
caused or mediated by the nervous system. Thus, it is possible to
reduce or avoid further damage to the health, such as a weakening
of the strength of the heart or sometimes fatal cardiac arrhythmias
such as ventricular fibrillation. By eliminating or reducing the
dysfunction of the autonomous nervous system, the compounds of the
formula I and their physiologically acceptable salts lead to a
normalization of the weakened strength of the heart and to the
prevention of the development of cardiac arrhythmias which can lead
to sudden cardiac death. Areas of use of the compounds of the
formula I and/or their physiologically acceptable salts in the
context of the present invention are therefore in particular also
the use in cases of cardiac insufficiency and the prevention of
cardiac arrhythmias such as fatal ventricular fibrillation and the
prevention of sudden cardiac death. By selecting compounds of the
formula I having a suitable activity profile with respect to the
direct effect on the heart (=direct effect on the action potential
of the heart muscle cells and accordingly direct effect on the
contractile force and direct antiarrhythmic effect) on the one hand
and the effect on the heart nerves on the other hand it is possible
in a particularly efficient manner to influence heart diseases
favorably with the aid of the compounds of the formula I. Depending
on the particular symptoms, it may also be advantageous to employ
compounds of the formula I which only have a relatively low direct
effect on the heart and accordingly only have, for example, a
relatively low direct effect on the contractile force of the heart
or the generation of arrhythmias, but which can improve or
normalize the strength of the heart or the heart rhythm by
influencing the autonomous nervous system. As already mentioned, an
impaired function of the vagal system and its consequences can also
occur temporarily, for example in the case of oxygen deficiency of
the heart. The compounds of the formula I are therefore also
particularly suitable for use in angina pectoris or coronary heart
disease where states of oxygen deficiency occur.
[0110] Furthermore, compounds of the formula I can generally be
employed in cases of dysfunctions of the autonomous nervous system,
in particular vagal dysfunction, which occur as a result of a
metabolic disorder, such as, for example, diabetes mellitus.
[0111] The compounds of the formula I and their physiologically
acceptable salts can therefore be used in animals, preferably
mammals and in particular humans as a medicament per se, in
mixtures with one another or together with other active compounds,
in particular in the form of pharmaceutical preparations (or
pharmaceutical compositions). A subject of the present invention
thus is the use of the compounds of the formula I and/or their
physiologically acceptable salts for preparing medicaments for the
therapy or prophylaxis of the abovementioned syndromes. A subject
of the invention also is the use of the compounds of the formula I
and/or their physiologically acceptable salts for the therapy or
prophylaxis of the abovementioned syndromes, and a subject of the
invention are methods for the therapy or prophylaxis of the
abovementioned syndromes in which an effective amount of one or
more compounds of the formula I and/or their physiologically
acceptable salts is administered to a human or animal patient in
need thereof.
[0112] Medicaments utilizable according to the invention which
comprise the compounds of the formula I and/or their
physiologically acceptable salts can be administered enterally, for
example orally or rectally, for example in the form of pills,
tablets, coated tablets, sugar-coated tablets, granules, hard and
soft gelatin capsules, suppositories, solutions, such as aqueous,
alcoholic or oily solutions, juices, drops, syrups, emulsions or
suspensions. The medicaments can also be administered parenterally,
for example subcutaneously, intramuscularly or intravenously in the
form of solutions for injection or solutions for infusion. Other
suitable administration forms are, for example, percutaneous or
topical application, for example in the form of ointments, creams,
pastes, lotions, gels, sprays, powders, foams, aerosols or
solutions, or the use in the form of implants.
[0113] The pharmaceutical preparations utilizable according to the
invention can be prepared by known standard processes for preparing
pharmaceutical preparations. To this end, one or more compounds of
the formula I and/or their physiologically acceptable salts are
mixed together with one or more solid or liquid pharmaceutical
excipients and/or additives or auxiliaries and, if a combination
preparation is desired, further pharmaceutically active compounds
having therapeutic or prophylactic effect, and brought into a
suitable administration form or dosage form which can then be used
as a medicament in human medicine or veterinary medicine. The
pharmaceutical preparations comprise a therapeutically or
prophylactically effective dose of the compounds of the formula I
and/or their physiologically acceptable salts, which normally is
from 0.5 to 90% by weight of the pharmaceutical preparation. The
amount of active compound of the formula I and/or its
physiologically acceptable salts in the pharmaceutical preparations
is generally from 0.2 mg to 1000 mg, preferably from 0.2 mg to 500
mg, particularly preferably from 1 mg to 500 mg, per unit but can
also be higher, depending on the nature of the pharmaceutical
preparation.
[0114] Suitable excipients are organic or inorganic substances
which are suitable, for example, for enteral (for example oral) or
parenteral (for example intravenous) administration or topical
administrations and which do not react with the active compounds in
an undesirable manner, for example water, vegetable oils, alcohols
such as ethanol, isopropanol or benzyl alcohols, 1,2-propanediol,
polyethylene glycols, glycerol triacetate, gelatin, carbohydrates,
such as lactose or starch, magnesium stearate, talc, lanolin,
petroleum jelly, acetonitrile, dimethylformamide,
dimethylacetamide. It is also possible to employ mixtures of two or
more excipients, for example mixtures of two or more solvents, in
particular also mixtures of one or more organic solvents with
water. As additives or auxiliaries, the pharmaceutical preparations
can contain, for example, stabilizers, wetting agents, emulsifiers,
solubilizers, thickeners, salts, for example for influencing the
osmotic pressure, glidants, preservatives, colorants, flavorings,
aromas and/or buffer substances. If desired, they can also comprise
one or more further active compounds, for example one or more
vitamins. It is also possible to lyophilize the compounds of the
formula I and/or their physiologically acceptable salts, and to use
the resulting lyophilisates for preparing preparations for
injection, for example. Also suitable are liposomal preparations,
in particular for topical administration.
[0115] The dosage of the active compound of the formula I to be
administered and/or of a physiologically acceptable salt thereof
when used according to the invention, depends on the individual
case and has to be adapted to the individual circumstances to
obtain an optimum effect, as is customary. It therefore depends on
the nature and the seriousness of the disease to be treated, and
also on the sex, the age, the weight and the individual
responsiveness of the human or animal to be treated, on the
effectiveness and the duration of action of the compounds used, on
whether the treatment is an acute or chronic therapy or
prophylaxis, or on whether other active compounds are administered
in addition to compounds of the formula I. In general, a dosage
range for the treatment of a dysfunction of the autonomous nervous
system in humans of from approximately 0.1 mg to approximately 100
mg per kg and day, when administered to an adult of a weight of
about 75 kg, is adequate for achieving the desired effect.
Preference is given to a dosage range of from approximately 1 mg to
approximately 10 mg per kg and day (in each case mg per kg of
bodyweight). The daily dose can be administered as a single dose or
be divided into more than one, for example two, three or four,
individual doses. It can also be administered continuously.
Depending on the individual behavior, it may be necessary to exceed
or reduce the stated daily dose.
[0116] In addition to the effect on the autonomous nervous system,
it has also been found that the compounds of the formula I have a
synergistic effect with beta-receptor blockers which can
advantageously be used in particular in the treatment and
prophylaxis of heart diseases such as, for example, cardiac
insufficiency. As is known, the use of beta-receptor blockers at
low doses improves the symptoms in cases of cardiac insufficiency
by depressing the sympathicus, whereas compounds of the formula I
reestablish the disrupted balance between vagal and sympathetic
nerves primarily via vagal stimulation. As demonstrated in the
animal experiment described below, a combination of compounds of
the formula I and beta-receptor blockers shows a superadditive or
synergistic effect in the prevention of heart diseases or heart
damage and is therefore particularly advantageously suitable, for
example, for improving the symptoms in cases of cardiac
insufficiency or for preventing or reducing cardiac arrhythmias,
such as ventricular fibrillation, or for preventing sudden cardiac
death. Expressed in a different way, the compounds of the formula I
significantly improve the effect of beta-receptor blockers, for
example on the heart. Thus, the compounds of the formula I are
highly suitable for combinations with beta-receptor blockers.
[0117] A subject of the present invention therefore also is the
treatment and prophylaxis of the abovementioned heart diseases such
as, for example, cardiac insufficiency, angina pectoris, cardiac
infarction, postmyocardial infarction or cardiac arrhythmias such
as ventricular fibrillation, or the prevention of sudden cardiac
death, and the treatment and prophylaxis of dysfunctions of the
autonomous nervous system, in particular vagal dysfunction,
specifically vagal dysfunction of the heart, by one or more
compounds of the formula I and/or their physiologically acceptable
salts in combination with one or more beta-receptor blockers and/or
their physiologically acceptable salts. A subject of the invention
also is the use of the compounds of the formula I and/or their
physiologically acceptable salts for preparing medicaments for such
a combination treatment or combination prophylaxis, and a subject
are methods for such combination therapy or combination
prophylaxis. A subject of the invention further are combinations of
one or more compounds of the formula I and/or their physiologically
acceptable salts and one or more beta-receptor blockers and/or
their physiologically acceptable salts for the simultaneous,
separate or sequential use in the conditions mentioned.
[0118] In the context of the combination treatment or combination
prophylaxis according to the invention, the representatives of the
two classes of active compounds can be administered in the form of
a pharmaceutical preparation where both of them together are
contained in the same pharmaceutical formulation unit, for example
a tablet, i.e. in the form of a pharmaceutical combination
preparation. But just so, they can be administered separately, for
example in the form of pharmaceutical preparations each containing
the representatives of only one of the two classes of the active
compounds, where in this case the representatives of the two
classes of active compounds can be administered simultaneously,
directly one after the other or sequentially including, for
example, after a relatively large interval. All these types are
embraced by the present invention. Depending on the circumstances
of the individual case, it may be more favorable to administer the
representatives of the two classes of active compounds in the form
of a pharmaceutical combination preparation in which they are
present together in a fixed ratio in the same pharmaceutical
formulation, or to administer them separately in the form of more
than one, for example two, individual pharmaceutical preparations
in each of which, for example, only a single active compound is
contained. In the latter case, the individual pharmaceutical
preparations, then forming a kit of parts, can in suitable primary
packaging be present together in a common external packaging, if
desired together with instructions for use referring to the
combination use according to the invention, or the individual
pharmaceutical preparations can be present in separate external
packagings, if desired in each case together with instructions for
use referring to the combination use according to the invention.
All such products and forms of presentation suitable for the use
according to the invention are embraced by the present
invention.
[0119] A subject of the present invention accordingly also are
products or articles, comprising one or more compounds of the
formula I 13
[0120] in which
[0121] R.sup.1 is hydrogen, methyl or trifluoromethyl;
[0122] R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl;
[0123] E is oxygen or sulfur;
[0124] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or
(C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4;
[0125] X is hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl;
[0126] Z is halogen, nitro, (C.sub.1-C.sub.4)-alkoxy or
(C.sub.1-C.sub.4)-alkyl;
[0127] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts, in
combination or as combination preparation with one or more
beta-receptor blockers and/or their physiologically acceptable
salts, for simultaneous, separate or sequential use in the
treatment or prophylaxis of dysfunctions of the autonomous nervous
system, a vagal dysfunction, a vagal dysfunction of the heart or in
the treatment or prophylaxis of the abovementioned diseases, in
particular heart diseases such as, for example, cardiac
insufficiency, angina pectoris, cardiac infarction, postmyocardial
infarction or cardiac arrhythmias such as ventricular fibrillation,
or in the prevention of sudden cardiac death.
[0128] A subject of the present invention in particular are the
pharmaceutical combination preparations mentioned in which the
representatives of the two classes of active compounds are present
together in the same pharmaceutical formulation, i.e.
pharmaceutical preparations which comprise one or more compounds of
the formula 14
[0129] in which
[0130] R.sup.1 is hydrogen, methyl or trifluoromethyl;
[0131] R.sup.2 is hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alko- xy-,
(C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-a-
lkoxy-, (C.sub.1-C.sub.6)-alkylthio, (C.sub.1-C.sub.6)-fluoroalkoxy
or (C.sub.1-C.sub.6)-fluoroalkyl;
[0132] E is oxygen or sulfur;
[0133] Y is a hydrocarbon residue of the formula
--(CR.sup.3.sub.2).sub.n-- - in which the residues R.sup.3
independently of one another are each hydrogen or
(C.sub.1-C.sub.2)-alkyl and n is 1, 2, 3 or 4;
[0134] X is hydrogen, halogen or (C.sub.1-C.sub.6)-alkyl;
[0135] Z is halogen, nitro, (C.sub.1-C.sub.4)-alkoxy or
(C.sub.1-C.sub.4)-alkyl;
[0136] in all their stereoisomeric forms and mixtures thereof in
all ratios, and/or their physiologically acceptable salts, one or
more beta-receptor blockers and/or their physiologically acceptable
salts and a physiologically acceptable carrier, i.e. one or more
physiologically acceptable excipients and/or additives or
auxiliaries.
[0137] All the above illustrations, for example with respect to
excipients, auxiliaries or additives, to pharmaceutical forms such
as tablets, sugar-coated tablets, capsules or solutions, and their
preparation, to possible administration forms, such as oral or
intravenous administration, to the use in human medicine and
veterinary medicine, or to the diseases which can be treated, etc.,
apply, correspondingly, to the products and pharmaceutical
preparations described above. In this context, the beta-receptor
blockers are to be considered as being an example of the further
pharmaceutically active compounds which, in addition to the
compounds of the formula I, may be present in the pharmaceutical
preparations mentioned further above. All the illustrations given
further above for the compounds of the formula I themselves also
apply, correspondingly, to the compounds of the formula I contained
in the products and the pharmaceutical preparations, for example
the illustrations with respect to the individual residues and
groups, to the preferred compounds of the formula I or to their
salts. In pharmaceutical preparations containing compounds of the
formula I together with beta-receptor blockers in the same
pharmaceutical formulation also salts may be present which are
formed by the compounds of these classes with one another, i.e.
salts which contain the beta-receptor blocker (or the beta-receptor
blockers), which are organic amino compounds, in protonated form as
cation and the compound (or the compounds) of the formula I in
deprotonated form as anion. The ratio by weight of the compounds of
the formula I to the beta-receptor blockers in the pharmaceutical
preparations in which both active compounds are present in the same
pharmaceutical formulation is generally from 500 to 0.02,
preferably from 100 to 0.1, parts by weight of the compound (or the
compounds) of the formula I per part by weight of the beta-receptor
blocker (or the beta-receptor blockers). For example, the ratio by
weight can be about 35 parts by weight of the compound of the
formula I per part by weight of the beta-receptor blocker, or it
can about 1 part by weight of the compound of the formula I per
part by weight of the beta-receptor blocker
[0138] As compounds of the formula 1, both the pharmaceutical
preparations to be used according to the invention which do not
contain any beta-receptor blockers and the products and the
pharmaceutical preparations according to the invention which do
contain beta-receptor blockers preferably comprise one or more of
the compounds selected from the group consisting of
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-me-
thoxyphenyl]sulfonyl]-3-methylthiourea,
1-[[5-[2-(5-chloro-2-methoxybenzam-
ido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthiourea and
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl-
]-3-methylthiourea and/or their physiologically acceptable salts,
preferred salts of these compounds being the sodium salts.
[0139] Suitable beta-receptor blockers for the combination
treatment and combination prophylaxis according to the invention
and for the products and pharmaceutical preparations according to
the invention are, for example, the following compounds:
alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol,
betaxolol, atenolol, acebutolol, metipranolol, propranolol,
nadolol, pindolol, timolol, sotalol, carvedilol, bisoprolol,
celiprolol, carazolol, talinolol, mepindolol, carteolol,
tertatolol, bopindolol. Preferred beta-receptor blockers are
propanolol, atenolol, bisoprolol and carvedilol.
[0140] When combining compounds of the formula I with beta-receptor
blockers, in general lower dosages of the compounds of the formula
I and/or the beta-receptor blockers are required to achieve the
desired effect than when the compounds of only one class of active
compounds are used. A preferred dosage of the compounds of the
formula I in combination with a beta-receptor blocker is in the
range from approximately 0.3 mg to approximately 15 mg, preferably
from approximately 1 mg to approximately 10 mg, per kg of
bodyweight and day. The dosage of the beta-receptor blockers in the
combination depends on the dosage customary for the individual
compound in question. Preference is given to using the lowest
customary dosage for the substance in question and the area of use
in question. The above illustrations with respect to the dosage of
the compounds of the formula I as individual active compounds
apply, correspondingly, to the combination use according to the
invention, for example with respect to the necessary adaptation of
the dosage to the circumstances of the individual case or to a
division of the dose into individual doses.
[0141] Owing to their effect on the autonomous nervous system, the
compounds of the formula I and their salts can be used not only as
pharmaceutically active compounds in human medicine and veterinary
medicine but also as a scientific tool or as an auxiliary for
biochemical investigations in which such an effect is intended, and
also for diagnostic purposes, for example in the in vitro diagnosis
of cell samples or tissue samples.
[0142] The present invention also provides the compounds of the
formula I per se which have hitherto not been described, and their
physiologically acceptable salts. In particular, the invention
provides the novel substances per se described in the working
examples, for example
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl-
]-3-methylthiourea and its physiologically acceptable salts
including its sodium salt, the use of the novel compounds as
pharmaceutically active compounds, and pharmaceutical preparations
which comprise one or more of these compounds and a physiologically
acceptable carrier, i.e. one or more physiologically acceptable
excipients and/or additives or auxiliaries. The above illustrations
apply correspondingly to these pharmaceutical preparations,
excipients and auxiliaries.
[0143] Besides the compounds described in the working examples, for
example also the compounds of the formula I compiled below can be
used according to the invention.
[0144] (1)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)propyl]-2-methoxyphen-
yl]sulfonyl]-3-methylthiourea
[0145] (2)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)butyl]-2-methoxypheny-
l]sulfonyl]-3-methylthiourea
[0146] (3)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethoxyphenyl-
]sulfonyl]-3-methylthiourea
[0147] (4)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-propoxypheny-
l]sulfonyl]-3-methylthiourea
[0148] (5)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethylphenyl]-
sulfonyl]-3-methylthiourea
[0149] (6)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methylphenyl-
]sulfonyl]-3-methylthiourea
[0150] (7)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-isopropylphe-
nyl]sulfonyl]-3-methylthiourea
[0151] (8)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-bromophenyl]-
sulfonyl]-3-methylthiourea
[0152] (9)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-fluorophenyl-
]sulfonyl]-3-methylthiourea
[0153] (10)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-trifluorome-
thoxyphenyl]sulfonyl]-3-methylthiourea
[0154] (11)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methylthiop-
henyl]sulfonyl]-3-methylthiourea
[0155] (12)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethylthioph-
enyl]sulfonyl]-3-methylthiourea
[0156] (13) 1
-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-isopropylp-
henyl]sulfonyl]-3-methylthiourea
[0157] (14)
1-[[5-[(5-tert-butyl-2-methoxybenzamido)methyl]-2-methoxypheny-
l]sulfonyl]-3-methylthiourea
[0158] (15)
1-[[5-[2-(5-(1,1-dimethylpropyl)-2-methoxybenzamido)ethyl]-2-m-
ethoxy-phenyl]sulfonyl]-3-methylthiourea
[0159] (16)
1-[[5-[2-(5-sec-butyl-2-methoxybenzamido)ethyl]-2-methoxypheny-
l]sulfonyl]-3-methylthiourea
[0160] (17)
1-[[5-[2-(5-n-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]-
sulfonyl]-3-methylthiourea
[0161] (18)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)propyl]-2-methoxyphe-
nyl]sulfonyl]-3-methylurea
[0162] (19)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)butyl]-2-methoxyphen-
yl]sulfonyl]-3-methylurea
[0163] (20)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethoxypheny-
l]sulfonyl]-3-methylurea
[0164] (21)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-propoxyphen-
yl]sulfonyl]-3-methylurea
[0165] (22)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethylphenyl-
]sulfonyl]-3-methylurea
[0166] (23)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methylpheny-
l]sulfonyl]-3-methylurea
[0167] (24)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-isopropylph-
enyl]sulfonyl]-3-methylurea
[0168] (25)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-bromophenyl-
]sulfonyl]-3-methylurea
[0169] (26)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-fluoropheny-
l]sulfonyl]-3-methylurea
[0170] (27)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-trifluorome-
thoxyphenyl]sulfonyl]-3-methylurea
[0171] (28)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methylthiop-
henyl]sulfonyl]-3-methylurea
[0172] (29)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-ethylthioph-
enyl]sulfonyl]-3-methylurea
[0173] (30)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-isopropoxyp-
henyl]sulfonyl]-3-methylurea
[0174] (31)
1-[[5-[(5-tert-butyl-2-methoxybenzamido)methyl]-2-methoxypheny-
l]sulfonyl]-3-methylurea
[0175] (32)
1-[[5-[2-(5-(1,1-dimethylpropyl)-2-methoxybenzamido)ethyl]-2-m-
ethoxyphenyl]sulfonyl]-3-methylurea
[0176] (33)
1-[[5-[2-(5-sec-butyl-2-methoxybenzamido)ethyl]-2-methoxypheny-
l]sulfonyl]-3-methylurea
[0177] (34)
1-[[5-[2-(5-n-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]-
sulfonyl]-3-methylurea
[0178] (35)
1-[[5-[2-(5-isopropyl-2-methoxybenzamido)ethyl]-2-methoxypheny-
l]sulfonyl]-3-methylurea
EXAMPLES
EXAMPLE 1
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-
-3-methylthiourea
[0179] 15
[0180] 0.286 g (0.68 mmol) of
5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-
-2-methoxybenzenesulfonamide were dissolved in 7.5 ml of
dimethylformamide and, after addition of 0.1 g of potassium
carbonate, admixed with 0.68 ml of a 1 M solution of methyl
isothiocyanate in dimethylformamide and stirred at 80.degree. C.
for 2 hours. The cooled reaction mixture was poured into dilute
aqueous hydrochloric acid, and the precipitate was filtered off
with suction and dried in the air. The product had a melting point
of 201-203.degree. C.
Preparation of the Starting Material
[0181] 1.51 g (10.0 mmol) of 2-(4-methoxyphenyl)ethylamine were
dissolved in 40 ml of pyridine and admixed with a spatula tip of
4-dimethylaminopyridine and then with a solution of 2.15 g (10.5
mmol) of 5-tert-butyl-2-methoxybenzoyl chloride. After the
2-(4-methoxyphenyl)ethy- lamine had been converted completely, the
reaction mixture was poured into cold dilute hydrochloric acid, and
the precipitated product was filtered off with suction and dried to
give 5-tert-butyl-2-methoxy-N-[2-(4-methoxy- phenyl)ethyl]benzamide
as a colorless solid. The benzamide was introduced into cold
chlorosulfonic acid. After the benzamide had been converted
completely, the reaction mixture was poured onto ice and filtered
off with suction, and the precipitate was dissolved in acetone.
This solution was admixed with excess concentrated aqueous ammonia.
After the exothermic reaction had subsided, the mixture was
concentrated to a third of its original volume and the precipitate
was filtered off with suction. The
5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxybenzenesulfonam-
ide was obtained in the form of colorless crystals of melting point
165-168.degree. C.
Example 2
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-
-3-methylurea
[0182] 16
[0183] 0.252 g (0.5 mmol) of
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)eth-
yl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (Example 1) were
dissolved in 2.5 ml of 2 N aqueous sodium hydroxide solution and
admixed with ice-cooling with 0.25 ml of 30% strength hydrogen
peroxide. The solution was stirred at room temperature for 24 h and
poured into a mixture of ice-water and 2 N hydrochloric acid.
Drying in the air gave white crystals of melting point
209-212.degree. C.
Example 3
1-[[5-[2-(5-Isopropyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]--
3-methylthiourea
[0184] 17
[0185] The preparation was carried out analogously to Example 1.
White crystals of melting point 177-179.degree. C. were
obtained.
Example 4
1-[[5-[2-(5-Chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-m-
ethylthiourea
[0186] 18
[0187] The preparation of this substance is described in U.S. Pat.
No. 5,574,069 (EP-A-612 724) which is incorporated herein by
reference and the contents of which regarding the preparation of
the substance are part of the present disclosure.
Example 5
1-[[5-[2-(5-Chloro-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sul-
fonyl]-3-methylthiourea
[0188] 19
[0189] The preparation of this substance is described in U.S. Pat.
No. 5,652,268 (EP-A-727 416) which is incorporated herein by
reference and the contents of which regarding the preparation of
the substance are part of the present disclosure.
Example 6
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl-
]sulfonyl]-3-methylthiourea
[0190] 20
[0191] The preparation was carried out analogously to Example 1
using
5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)benzenesu-
lfonamide. Instead of potassium carbonate, sodium hydride was used
as base in the reaction with methyl isothiocyanate analogously to
Example 5. The product had a melting point of 61.degree. C.
Example 7
1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-
-3-methylthiourea sodium salt
[0192] 21
[0193] 4.93 g of
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methox-
yphenyl]sulfonyl]-3-methylthiourea (Example 1) were introduced into
32 ml of methanol in which 0.425 g of solid sodium hydroxide had
been dissolved before. After 15 min of stirring, 125 ml of methyl
tert-butyl ether were added to the clear solution. With stirring,
the sodium salt was allowed to crystallize out and then filtered
off with suction, washed with a little cold methyl tert-butyl ether
and dried. Yield 5.09 g. Melting point: 235-250.degree. C.
(decomposition). IR spectrum (Nujol): 1646.1 cm.sup.-1.
Examples of Pharmaceutical Preparations
Example A
Tablet
[0194] To prepare tablets,
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2--
methoxyphenyl]sulfonyl]-3-methylthiourea (Example 4),
low-substituted hydroxypropylcellulose (L-HPC),
polyvinylpyrrolidone (Povidone 25) and croscarmellose sodium
(crosslinked sodium carboxymethylcellulose) were granulated
moistened with water. The granules were passed through a 1-1.5 mm
sieve, mixed with croscarmellose sodium and magnesium stearate and
compacted to tablets.
1 Amounts per tablet: Compound of Example 4 600 mg L-HPC 95 mg
Povidone 25 15 mg Croscarmellose sodium 60 mg Magnesium stearate 20
mg
Example B
Aqueous Solution for Intravenous Administration
[0195] To prepare 10 ml of solution comprising 10 mg of active
compound per ml, 100 mg of the sodium salt of
1-[[5-[2-(5-chloro-2-methoxybenzamid-
o)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (see Example 4)
were dissolved in 10 ml of isotonic (0.9% strength) sodium chloride
solution.
Pharmacological Investigations
[0196] 1. Effect on Vagal Dysfunction
[0197] The substances were investigated using the model of
chloroform-induced ventricular fibrillation in the mouse (see J. W.
Lawson, Antiarrhythmic activity of some isoquinoline derivatives
determined by a rapid screening procedure in the mouse; J.
Pharmacol. Exp. Ther. 1968, 160, 22-31). The test substance was
dissolved in a mixture of dimethyl sulfoxide (DMSO) and 10%
strength sodium bicarbonate solution and administered
intraperitoneally (i.p.). After 30 minutes, the mouse was
anesthetized with chloroform in a beaker. As soon as, in deep
anesthesia, respiratory arrest had occurred (toxic anesthesia
stage), the thorax of the animal was opened using a pair of
scissors and the heartbeat was inspected visually. Here, it is
possible to determine on first sight whether the heart is beating,
fibrillating or arrested. The respiratory arrest triggered by
chloroform leads, via absolute anoxia (lack of oxygen) in
combination with a direct stimulating effect of chloroform on the
sympathetic nervous system, to a potent stimulation of the
sympathicus, which in turn in combination with the energy deficit
in the heart caused by lack of oxygen results in fatal arrhythmia,
i.e. ventricular fibrillation. This toxic chloroform anesthesia led
to ventricular fibrillation in 100% of the untreated mice
(control). The percentage of the mice with ventricular fibrillation
in the individual test groups is shown in Table 1.
2TABLE 1 Chloroform-induced ventricular fibrillation in the mouse
Proportion of fibrillation (in %) without with atropine Substance
(dose) atropine (1 mg/kg i.v.) untreated control 100% 100% Example
1 (3 mg/kg i.p.) 30%# 90%* Example 2 (1 mg/kg i.p.) 60%# 100%*
Example 3 (3 mg/kg i.p.) 60%# 1-[[5-[2-(5-chloro-2-methoxybenzami-
do)ethyl]- 50%# 90%* 2-methoxyphenyl]sulfonyl]-3-methylthiourea
sodium salt (see Example 4) (10 mg/kg i.p.) Example 5 (10 mg/kg
i.p.) 60%# 100%* carbachol (60 .mu.g/kg i.v.) 60%# 100%*
physostigmine (1 mg/kg s.c.) 70%# 100%* #significant inhibition of
ventricular fibrillation by the substances (n = 10) compared to #
control animals (n = 300), p < 0.005 *significant reduction of
the protective effect of the substances by atropine (n = 10), p
< 0.05
[0198] The results show that the compounds of the formula I
significantly reduce the occurrence of ventricular fibrillation.
The observed influence of atropine, the classic blocker of
muscarinic (vagal) receptors of the autonomous nervous system,
which blocks the effect of the vagal transmitter acetylcholine on
the receptor level, gives an indication of the mechanism of action.
Atropine reduces or prevents the protective effect of the compounds
of the formula I. This neutralization of the protective effect of
the substances by atropine points unambiguously to a vagal
mechanism of action. A similar protective effect could be generated
by vagal stimulation with carbachol, a more stable analog of the
natural vagal transmitter acetylcholine, where the protective
effect could likewise be inhibited by atropine. Furthermore, the
cholinesterase inhibitor physostigmine, which slows down the
degradation of acetylcholine, mimicked the protective effect of the
compounds of the formula I, an effect which was likewise
neutralized by atropine.
[0199] 2. Effect of Combinations of Compounds of the Formula I with
Beta-receptor Blockers
[0200] In the same animal model as in the experiment "effect on
vagal dysfunction" described above, it was demonstrated that a
combined treatment with beta-receptor blockers and compounds of the
formula I results in a favorable synergistic effect. The active
compounds were administered i.v. (intravenously) or i.p.
(intraperitoneally). In one experiment, 10 mg/kg of
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-me-
thoxyphenyl]sulfonyl]-3-methylthiourea sodium salt (see Example 4;
dissolved in DMSO/10% strength sodium bicarbonate solution) were
combined with 0.3 mg/kg of propanolol (dissolved in distilled
water), a standard beta-blocker. It was found that the combined
pretreatment of the animals with the two substances had a
synergistic effect. The proportion of fibrillation could be lowered
further than with the individual substances, in a statistically
significant manner. For comparison, a 10 times higher dose of 3
mg/kg of propanolol was used. It was found that 0.3 mg/kg of
propanolol in combination with 10 mg/kg of
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3--
methylthiourea sodium salt gave approximately the same result as 3
mg/kg of propranolol, or was even superior to the effect of a
propanolol dose of 3 mg/kg. In another experiment, 3 mg/kg of
1-[[5-[2-(5-tert-butyl-2-me-
thoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea
(Example 1) and 3 mg/kg of atenolol were combined in an analogous
manner. The results of the combination treatments are shown in
Table 2.
3TABLE 2 Synergistic effect of compounds of the formula I and
beta-receptor blockers Proportion of Substance (Dose) fibrillation
in % untreated control (n = 100) 100%
1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]- 50%*
2-methoxyphenyl]sulfonyl]-3-methylthiourea sodium salt (see Example
4) (10 mg/kg i.v.) propranolol (0.3 mg/kg i.v.) 37%* propranolol (3
mg/kg i.v.) 17%* 1-[[5-[2-(5-chloro-2-methoxybenza- mido)ethyl]-
10%*# 2-methoxyphenyl]sulfonyl]-3-methylthiourea sodium salt (10
mg/kg i.v.) plus propranolol (0.3 mg/kg i.v.)
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]- 53%*
2-methoxyphenyl]sulfonyl]-3-methylthiourea (Example 1) (3 mg/kg
i.p.) atenolol (3 mg/kg i.v.) 48%* 1-[[5-[2-(5-tert-butyl-2-
-methoxybenzamido)ethyl]- 25%*#
2-methoxyphenyl]sulfonyl]-3-methylt- hiourea (3 mg/kg i.p.) plus
atenolol (3 mg/kg i.v.) *p < 0.001 vs. untreated control; #p
< 0.05 vs. beta-receptor blocker or compound of the formula I; n
= 30 for all treated groups.
* * * * *