Potassium channel inhibitors

Details Potassium channel inhibitors Potassium channel inhibitors

2000-10-13

2002-05-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S227200, C544S054000

Reexamination Certificate

active

06395730

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is broadly directed to a class of thiazolidinone and metathiazanone compounds and their derivatives useful as potassium channel inhibitors.
2. Description of Related Art
Potassium channels are expressed in eukaryotic and procaryotic cells, and are elements in the control of electrical and nonelectrical cellular functions. Subclasses of these channels have been named based on amino acid sequence and functional properties, and include for example voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, “Voltage-gated potassium channel genes” in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al.,
Curr. Opin. Neurobiol.
5:268, 1995).
Inhibitors of potassium channels lead to a decrease in potassium ion movement across cell membranes. Consequently, such inhibitors induce prolongation of the electrical action potential or membrane potential depolarization in cells containing the inhibited or blocked potassium channels. Prolonging of the electrical action potential is a preferred mechanism for treating certain diseases, e.g., cardiac arrhythmias (Colatsky et al.,
Circulation
82:2235, 1990). Membrane potential depolarization is a preferred mechanism for the treating of certain other diseases, such as those involving the immune system (Kaczorowski and Koo,
Perspectives in Drug Discovery and Design,
2:233, 1994).
Potassium channels which exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states. For example, the delayed rectifier voltage-gated potassium channel termed I
kur
or I
sus
which has been reported to contain the Kv1.5 &agr;-subunit gene product is generally believed to be important in the repolarization of the human atrial action potential and thus is a candidate potassium channel target for the treatment of cardiac arrhythmias especially those occurring in the atria (Wang et al.,
Circ. Res.
73:1061, 1993; Fedida et al.,
Circ. Res.
73:210, 1993; Wang et al.,
J. Pharmacol Exp. Ther.
272:184, 1995; Amos et al.,
J. Physiol,
491:31, 1996).
The present invention is related to thiazolidinone and metathiazanone compounds which have been found to be useful as inhibitors of potassium channel function. Such compounds have been found to be especially active as inhibitors of voltage-gated potassium channels and may therefore be utilized for the treatment of diseases, conditions and disorders in which prolongation of cellular action potentials or the induction of cell membrane depolarization would be beneficial. These disease states, conditions and disorders include, but are not limited to cardiac arrhythmias, cell proliferative disorders including cancer, disorders of the auditory system, central nervous system mediated motor dysfunction and disorders of pulmonary, vascular and visceral smooth muscle contractility.
It is an object of the present invention, therefore, to provide a method of treating diseases, conditions and disorders in mammals, including humans, which respond to the inhibition of potassium channel function, which method comprises administering to a mammal in need thereof certain thiazolidinone or metathiazanone compounds.
Another object of the invention is to provide certain thiazolidinone and metathiazanone compounds which are useful for the treatment of such diseases, conditions and disorders in mammals, including humans.
DETAILED DESCRIPTION OF THE INVENTION
This invention describes certain thiazolidinone and metathiazanone compounds and their utility as inhibitors of voltage-dependent potassium channel function, particularly potassium channels (i.e., I
Kur
, Kv1.5) that could serve as targets for the treatment of cardiac arrhythmias especially those occurring in the atria (e.g., atrial flutter and atrial fibrillation) (Wang et al.,
Circ. Res.
73:1061, 1993; Fedida et al.,
Circ. Res.
73:210, 1993; Wang et al.,
J. Pharmacol. Exp. Ther.
272:184, 1995), as well as the potassium channels that could serve as targets for the treatment of immunologic diseases and conditions and disorders of the nervous system and the gastrointestinal system. Consequently, the present invention also provides a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function such as cardiac arrhythmias and various immunologic, nervous and gatrointestinal diseases using certain thiazolidinone and metathiazanone compounds.
The invention is particularly based on the discovery that thiazolidinone and metathiazanone compounds of the following formula (I), and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, are inhibitors of potassium channel function. In particular, these thiazolidinone and metathiazanone compounds have demonstrated activity against the human potassium channels/currents I
Kur
, Kv1.5. As a result, these compounds are useful in the treatment inter alia, of cardiac arrhythmias and other diseases, conditions and disorders.
Thus, in a first aspect, the present invention concerns a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function by using a compound having the formula (I) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof:
wherein,
v is 0 or 1;
t is 0, 1, or 2;
X in an orientation R
1
—X—, is selected from —(CR
4
2
)
p
—; —(CR
4
2
)
m
O(CR
4
2
)
n
—; —(CR
4
2
)
m
CH═CH(CR
4
2
)
s
—;—(CR
4
2
)
m
CH≡CH(CR
4
2
)
s
—; —(CR
4
2
)
m
—A—(CR
4
2
)
m
—;
—(CR
4
2
)
m
—NR
4
—(CR
4
2
)
n
—;
 where p is an integer of 0 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A is selected from an optionally substituted 3 to 7 membered carbocyclic ring and an optionally substituted 5 to 7 membered heterocyclic ring; each R
4
is independently selected from H, a lower alkyl, an aryl and a heteroaryl; W is selected from O and NR
5
where R
5
is selected from H, lower alkyl, aryl, C≡N and NHR
4
;
R
1
is selected from H, an optionally substituted aryl and an optionally substituted heteroaryl;
Y, in an orientation R
2
—Y—, is selected from —(CR
4
2
)
q
—; —(CR
4
2
)
m
O(CR
4
2
)
n
—; —(CR
4
2
)
m
CH═CH(CR
4
2
)
m
—; —(CR
4
2
)
m
CH≡CH(CR
4
2
)
m
—; —(CR
4
2
)
m
—A—(CR
4
2
)
m
— and a cycloalkyl, where q is an integer of 0 to 4 and m and n are as defined above;
R
2
is selected from H, an optionally substituted aryl and an optionally substituted heteroaryl; and
R
3
is selected from H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl and —NR
6
R
7
, where R
6
is selected from H and optionally substituted lower alkyl; R
7
is H, optionally substituted lower alkyl, optionally substituted aryl, —(SO
2
)R
8
, —COR
8
and —C(O)NH—R
4
, R
8
is selected from optionally substituted lower alkyl, optionally substituted aryl and optionally substituted heteroaryl or R
6
and R
7
together with the nitrogen to which they are attached form a heteroaryl.
When v is 1, formula (I) relates to a class of metathiazanone compounds of the following formula, with the various variables as defined above:
When v is 0, formula (I) relates to a class of thiazolidinone compounds of the following formula, with the various variables as defined above:
In a preferred aspect, the present invention concerns a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function by using a compound h

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