Potassium channel inhibitors

Details Potassium channel inhibitors Potassium channel inhibitors

1999-01-13

2001-12-25

O'Sullivan, Peter (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S311000, C514S319000, C514S355000, C514S357000, C514S455000, C514S448000, C514S466000, C514S524000, C514S602000, C514S603000, C514S821000, C546S146000, C546S166000, C546S206000, C546S293000, C549S065000, C549S072000, C549S436000, C558S413000, C564S084000, C564S085000, C564S086000, C564S087000, C564S088000, C564S089000

Reexamination Certificate

active

06333337

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is broadly directed to a class of compounds 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 directed to compounds which are useful as inhibitors of potassium channel function.
It is an object of the present invention, therefore, to provide compounds which are useful for the treatment of diseases in mammals, including humans, and especially for the management of diseases which can be treated by inhibiting cell membrane potassium channels.
Another object of the invention is to provide a method of treating diseases in mammals, including humans, which respond to the inhibition of potassium channel function, which method comprises administering to a mammal in need thereof a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
This invention describes compounds and their utility as inhibitors of potassium channel function. The invention is particularly directed to compounds that inhibit potassium channels which could serve as targets for the treatment of cardiac arrhythmias (i.e., I
Kur
, Kv1.5) 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). The present invention also provides a method for treating diseases which respond to the inhibition of potassium channel function. These 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.
The invention is particularly based on our discovery that the compounds of the following formula (I) are inhibitors of potassium channel function and are thus useful for inhibiting potassium transport across cellular membranes and for treating cardiac arrhythmias. In particular, these compounds have demonstrated activity against human potassium channels.
Thus, this aspect of the present invention concerns such methods and such compounds having potassium channel inhibitory activity of the formula (I) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof:
wherein t is 1, or 2;
A and B are each H, or taken together form a bond between the substituted carbons;
R
1
is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;
Y
2
is (CH
2
)
q
, (CH
2
)
w
O, HC═CH, ethynyl or NH, w is 0, 1, or 2 and q is 0, 1, or 2, with the proviso that if Y
2
is (CH
2
)
q
and q=0, then R
1
cannot be H;
X
2
is C═O, C═S, or SO
2
; with the proviso that if Y
2
is (CH
2
)
w
O, then X
2
is not SO
2
;
R
3
is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl; an optionally substituted heterocycle, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino);
Z is H, alkyl, alkyenyl, alkylene(heterocyclyl), alkylene(heteroaryl), alkylene-NHC(O)(alkyl), alkylene-NHC(O)(aryl), alkylene-NHC(O)(heterocyclyl), alkylene-NHC(O)(heteroaryl), alkylene-NHC(O)-(alkylene-heterocyclyl), alkylene-NHC(O)-(heteroarayl), alkylene-C(O)(alkyl), alkylene-C(O)O(alkyl), OR
14
, SR
14
or NR
15
R
16
; where R
14
is selected from the group consisting of H, (CH
2
)
m
—R
8
, or C(O)—(CH
2
)
r
—R
8
; m is 1, 2, 3, or 4; r is 0, 1, 2, or 3; R
8
is CH
2
N(R
9
)
2
, CH
2
N(R
9
)
3
L, or CO
2
R
9
; each R
9
is independently selected from H, or alkyl; L is a counter ion; R
15
is H, or alkyl; and R
16
is H, alkyl or CO
2
R
10
and R
10
is H, or alkyl;
R
2
is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, an optionally substituted carbocycloalkyl, R
a
—O—, and R
b
R
c
—N—; where R
a
and R
b
are independently selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl; R
c
is selected from the group consisting of H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted heteroaralkyl, and an optionally substituted carbocycloalkyl; or R
b
and R
c
along with the nitrogen to which they are attached form a heterocyclyl;
Y
1
is (CH
2
)
p
, CHR
17
(CH
2
)
o
, HC═CH, or ethynyl; where R
17
is alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl; p is 0, 1, 2 or 3; and o is 0, 1 or 2;
X
1
is C═O, C═S, SO
2
or (CH
2
)
n
; where n is 0, 1, or 2;
R
4
is H, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl; an optionally substituted heterocycle, an optionally substituted heterocyclyl, an optionally substituted carbocycloalkyl, or an alkylene-(substituted amino); and
with the provisos (i) that if Y
1
is (CH
2
)
p
, p is 0 and X
1
is not (CH
2
)
n
, then R
2
is not H, (ii) that if R
2
is R
a
—O and Y
1
is (CH
2
)
p

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