2,5-substituted benzolsulfonylureas and thioureas methods...

Details 2,5-substituted benzolsulfonylureas and thioureas methods... 2,5-substituted benzolsulfonylureas and thioureas methods...

2001-01-16

2002-06-25

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S438000, C514S461000, C514S592000, C549S077000, C549S496000, C546S331000, C546S332000, C564S047000

Reexamination Certificate

active

06410573

ABSTRACT:

The present invention relates to novel 2,5-substituted benzenesulfonylureas and -thioureas of the formula I
in which R(1), R(2), R(3), R(4), X and Y have the meanings indicated below, which are valuable pharmaceutical active compounds. The compounds of the formula I have an inhibitory action on ATP-sensitive potassium channels and are suitable, for example, for the treatment of disorders of the cardiovascular system, in particular for the treatment of arrhythmias, for the prevention of sudden heart death or for affecting decreased contractility of the heart. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical preparations comprising them.
A hypoglycemic action is described for certain benzenesulfonylureas. Glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus, counts as a prototype of hypoglycemic sulfonylureas of this type. Glibenclamide blocks ATP-sensitive potassium channels and is used in research as a tool for the exploration of potassium channels of this type. In addition to its hypoglycemic action, glibenclamide additionally possesses other actions which are attributed to the blockade of precisely these ATP-sensitive potassium channels, which as yet, however, still cannot be utilized therapeutically. These include, in particular, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide, however, the hypoglycemia simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient.
The patent applications EP-A-612 724, EP-A-657 423, EP-A-661 264, EP-A-726 250, EP-A-727 416, EP-A-727 417 and EP-A-728 741 disclose antifibrillatory benzenesulfonylureas and -thioureas having decreased hypoglycemic action. The properties of these compounds, however, are still not satisfactory in various respects, and there furthermore exists a need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile, which are better suited, in particular, to the treatment of a disturbed heart rhythm and its consequences. Surprisingly, it has now been found that certain 2,5-substituted benzenesulfonylureas and -thioureas which contain an unsaturated radical in the 2-position are distinguished by a marked action on ATP-sensitive potassium channels.
The present invention thus relates to compounds of the formula I
in which
X is oxygen or sulfur;
Y is —(CR(5)
2
)
n
—;
R(1) is
1. phenyl which is unsubstituted or is substituted by one or two identical or different substituents from the group consisting of halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, —S(O)
m
—(C
1
-C
4
)-alkyl, phenyl, amino, hydroxyl, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, (C
1
-C
4
)-alkoxycarbonyl and formyl; or
2. naphthyl; or
3. monocyclic or bicyclic heteroaryl having one or two identical or different ring heteroatoms from the group consisting of oxygen, sulfur and nitrogen; or
4. —S(O)
m
-phenyl; or
5. (C
2
-C
5
)-alkenyl which is unsubstituted or is substituted by a radical from the group consisting of phenyl, cyano, hydroxycarbonyl and (C
1
-C
4
)-alkoxycarbonyl; or
6. (C
2
-C
5
)-alkynyl which is unsubstituted or is substituted by a radical from the group consisting of phenyl and (C
1
-C
4
)-alkoxy;
R(2) is hydrogen or (C
1
-C
3
)-alkyl;
R(3) and R(4) independently of one another are hydrogen, halogen or (C
1
-C
4
)-alkoxy;
the radicals R(5), which are all independent of one another and can be identical or different, are hydrogen or (C
1
-C
3
)-alkyl;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
If radicals, groups, substituents or variables can occur a number of times in the compounds of the formula I, they can all independently of one another have the meanings indicated and can in each case be identical or different.
The term alkyl, if not stated otherwise, denotes straight-chain or branched saturated hydrocarbon radicals. This also applies to radicals derived therefrom such as, for example, alkoxy, alkoxycarbonyl or —S(O)
m
-alkyl. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy or isopropoxy.
Alkenyl and alkynyl represent straight-chain or branched, mono- or polyunsaturated hydrocarbon radicals, in which the double bonds and/or triple bonds can be situated in any desired positions. Examples of alkenyl and alkynyl are vinyl, prop-2-enyl (allyl), prop-1-enyl, butenyl, 3-methylbut-2-enyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl and but-3-ynyl.
Halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine.
In substituted phenyl radicals, the substituents can be situated in any desired positions. In monosubstituted phenyl radicals, the substituent can be situated in the 2-position, the 3-position or the 4-position; in disubstituted phenyl radicals, the substituents can be situated in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. If a phenyl radical carries a further phenyl radical as a substituent, this phenyl radical in turn can also be unsubstituted or can be substituted by one or two identical or different radicals of the type which are mentioned as substituents on the first phenyl radical, except by a phenyl radical. Naphthyl can be 1-naphthyl or 2-naphthyl.
Heteroaryl is understood as meaning radicals of monocyclic or bicyclic aromatic ring systems, which in the case of the monocyclic systems have a 5-membered ring or a 6-membered ring and in the case of the bicyclic systems have two fused 5-membered rings, a 6-membered ring fused to a 5-membered ring or two fused 6membered rings. They can be conceived as being radicals derived from cyclopentadienyl, phenyl, pentalenyl, indenyl or naphthyl by replacement of one or two CH groups and/or CH
2
groups by S, O, N, NH (or N carrying a substituent such as, for example, N—CH
3
), where the aromatic ring system is retained or an aromatic ring system is formed. In addition to the one or two ring heteroatoms, they contain three to nine ring carbon atoms. Examples of heteroaryl are, in particular, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1,3-oxazolyl, 1,2-oxazolyl, 1,3-thiazolyl, 1,2-thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidyl, indolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl or benzopyranyl. A heteroaryl radical can be bonded via any suitable carbon atom. For example, a thienyl radical can be present as a 2-thienyl radical or 3-thienyl radical, a furyl radical as a 2-furyl radical or 3-furyl radical, a pyridyl radical as a 2-pyridyl radical, 3-pyridyl radical or 4-pyridyl radical. A radical which is derived from 1,3-thiazole or from imidazole can be bonded via the 2-position, the 4-position or the 5-position. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts having an anion derived from a physiologically tolerable acid as a counterion. Pyridyl radicals can thus be present, for example, as pyridine N-oxides.
The present invention includes all stereoisomeric forms of the compounds of the formula I. Asymmetric centers present in the compounds of the formula I can all independently of one another have the S configuration or the R configuration. The invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers are thus a subject of the invention 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. In the presence of cis/trans isomerism, both the cis form and the trans form and mixtures of these forms in all ratios are a subject of the invention. The preparation of ind

Affiliated with

Also associated with

Rating

2,5-substituted benzolsulfonylureas and thioureas methods... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 2,5-substituted benzolsulfonylureas and thioureas methods..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2,5-substituted benzolsulfonylureas and thioureas methods... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2904461