Substituted benzenesulfonylureas and -thioureas-processes...

Details Substituted benzenesulfonylureas and -thioureas-processes... Substituted benzenesulfonylureas and -thioureas-processes...

2001-11-29

2003-01-14

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S023000, C564S039000, C564S040000, C564S041000, C564S087000, C564S088000, C564S166000, C564S170000, C564S176000, C564S177000, C564S185000, C564S186000

Reexamination Certificate

active

06506937

ABSTRACT:

DESCRIPTION
Substituted benzenesulfonylureas and -thioureas-processes for their preparation and their use as pharmaceuticals.
The invention relates to substituted benzenesulfonylureas and -thioureas I
in which
R(1) is hydrogen, methyl, CH
2
F, CHF
2
or trifluoromethyl,
R(2) is hydrogen, F, Cl, Br, I, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-mercaptoalkyl, (C
1
-C
6
)-fluoroalkoxy or (C
1
-C
6
)-fluoroalkyl,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula:
—[CR(3)
2
]
n
—
where R(3) ═H or (C
1
-C
2
)-alkyl and n=1, 2, 3 or 4,
X is hydrogen, F, Cl, Br, I or (C
1
-C
6
)-alkyl and
Z is F, Cl, Br, I, NO
2
, (C
1
-C
4
)-alkoxy or (C
1
-C
4
)-alkyl.
Unless stated otherwise, the term alkyl describes straight-chain, branched or cyclic saturated hydrocarbon radicals having one to six carbon atoms. The cycloalkyl radical can additionally carry alkyl or trifluoromethyl substituents. The term alkoxy represents an other substituent having a straight-chain, branched or cyclic saturated hydrocarbon radical of one to six carbon atoms. Fluoroalkyl describes a straight-chain, branched or cyclic saturated carbon skeleton of one to six carbon atoms, in which at least one hydrogen atom of the alkyl radical defined above is replaced by fluorine, but a maximum of perfluoro-substitution is reached. Fluoro-alkoxy is understood as meaning an other substituent which carries a fluoroalkyl radical according to the above definition. The elements fluorine, chlorine, bromine and iodine can be employed as the halogen substituent. Compounds having centers of chirality in the alkyl side chain Y furthermore may occur. In this case, both the individual antipodes in themselves and a mixture of the enantiomers or diastereomers in various ratios, as well as the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers, belong to the invention.
Similar sulfonylureas are known from German Offenlegungs-schrift 2 413 514 and German Patent 1 518 874. DE-A 2 413 514 describes exclusively blood sugar-conditioning substances with p-substitution in the central phenyl group. There are no references to m-substitution or an amino substituent.
DE-C 1 518 874 describes hypoglycemic sulfonylureas of the formula
in which the central phenyl group can indeed also be m-substituted and trisubstituted, but in which R(1) can only be (C
2
-C
8
)-alkyl (in addition to many other meanings), and in which R(1) can never be a C
1
substituent or hydrogen.
The hypoglycemic action thereof in described in both patent publications. The prototype of such hypoglycemic sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus and is used in science as a much-regarded tool for researching so-called ATP-sensitive potassium channels. In addition to its hypoglycemic action, glibenclamide also has other actions which it has so far not yet been possible to employ therapeutically but which are all attributed to blockade precisely of those ATP-sensitive potassium channels. These include, in particular, an antifibrillatory action on the heart. However, simultaneous lowering of blood sugar would be undesirable or even dangerous during treatment of ventricular fibrillation or its preliminary stages, since it may deteriorate the condition of the patient further.
The object of the present invention was therefore to synthesize compounds which have a cardiac action which is equally as good an that of glibenclamide, but do not influence, or influence to a significantly lesser degree than glibenclamide, the blood sugar in cardioactive doses or concentrations.
Suitable test animals for detection of such actions are, for example, mice, rats, guineapigs, rabbits, dogs, monkeys or pigs.
The compounds I are used as medicament active compounds in human and veterinary medicine. They can furthermore be used as intermediate products for the preparation of other medicament active compounds.
Preferred compounds are those in which
R(1) is hydrogen, methyl or trifluoromethyl,
R(2) is hydrogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
4
)-mercaptoalkyl, (C
1
-C
6
)-fluoroalkyl, (C
1
-C
6
)-fluoroalkoxy or F, Cl, Br or I,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula —[CR(3)
2
]
n
—, where R(3)=H or C
1
-C
2
)-alkyl and n=1, 2, 3 or 4,
X is hydrogen, F, Cl or (C
1
-C
4
)-alkyl and
Z is nitro, F, Cl, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy.
Particularly preferred compounds I are those in which:
R(1) is hydrogen or methyl,
R(2) is (C
1
-C
6
)-alkyl or (C
1
-C
6
)-alkoxy,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula: —[R(3)
2
]
n
—, where R(3)=H or (C
1
-C
2
)-alkyl and n=1, 2, 3 or 4,
X is hydrogen, F, Cl or (C
1
-C
4
)-alkyl and
Z is chlorine or fluorine, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy.
Especially preferred compounds I are those in which:
R(1) is hydrogen or methyl, and
R(2) is hydrogen, fluorine or chlorine,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula: —[R(3)
2
]
n
—, where R(3)=H or (C
1
-C
2
)-alkyl and n=1, 2, 3 or 4,
X is hydrogen, F, Cl or (C
1
-C
4
)-alkyl, and
Z is chlorine, fluorine, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy.
Compounds I which are likewise particularly preferred are those in which
R(1) is hydrogen or methyl,
R(2) is (C
1
-C
6
)-fluoroalkyl, (C
1
-C
6
)-fluoroalkoxy or (C
1
-C
6
)-mercaptoalkyl,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula: —[CR(3)
2
]
n
— where R(3)=H or (C
1
-C
2
)-alkyl and n=1, 2, 3 or 4,
X is hydrogen, F, Cl or (C
1
-C
4
)-alkyl and
Z is chlorine, fluorine, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy.
Particularly preferred compounds I are those in which:
R(1) is hydrogen or methyl,
R(2) is methoxy or methyl,
E is oxygen or sulfur,
Y is a hydrocarbon chain of the formula: —[CR(3)
2
]
n
— where R(3)=H or methyl and n=2 or 3,
X is hydrogen, F, Cl or (C
1
-C
3
)-alkyl and
Z is chlorine or fluorine, (C
1
-C
3
)-alkyl or (C
1
-C
3
)-alkoxy.
The compounds I of the present invention are useful medicaments for the treatment of disturbances in cardiac rhythm of widely varying origin and for prevention of sudden cardiac death caused by arrhythmia, and can therefore be used as antiarrhythmics. Examples of arrhythmic disturbances of the heart are supraventricular disturbances in rhythm, such as, for example, auricular tachycardia, auricular flutter or paroxysmal supraventricular disturbances in rhythm, or ventricular disturbances in rhythm, such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardias or the particularly dangerous ventricular fibrillation. They are particularly suitable for those cases where arrhythmias are a consequence of a narrowing of a coronary vessel, such as occur, for example, with angina pectoris or during an acute cardiac infarction or as a chronic consequence of a cardiac infarction. They are therefore particularly suitable for prevention of sudden cardiac death in post-infarction patients. Other syndromes in which such disturbances in rhythm and/or sudden cardiac death caused by arrhythmia play a role are, for example, cardiac insufficiency or cardiac hypertrophy as a consequence of a chronically increased blood pressure.
The compounds I furthermore can positively influence a reduced contractility of the heart. This can be a disease-related decrease in cardiac contractility, for example in cases of cardiac insufficiency, or acute cases, such as cardiac failure under the effects of shock. In cases of a heart transplant, the heart likewise can resume its efficiency faster and more reliably after the operation has been performed. The same applies to operations on the heart which necessitate temporary stopping of cardiac activity by cardioplegic solutions, it being possible for the compounds to be used both for protection of the organs in the donor before and during removal, for protection of removed organs, for example during treatment with or storage thereof

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