Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-04
2002-04-16
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S290000, C546S298000, C546S305000, C546S306000, C546S309000
Reexamination Certificate
active
06372767
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of benzanilides as potassium channel openers and to the treatment of diseases modulated by potassium channel opening. Additionally, this invention relates to novel compounds that are useful as potassium channel openers.
BACKGROUND OF THE INVENTION
Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels are present in all human cells and affect such processes as nerve transmission, muscle contraction and cellular secretion. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.
Potassium channels have now been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport.
Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities (Wei et al.,
Neuropharmacology
35(7):805-829 (1997)). Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage. Two other families, CNG and SK/IK, also contain this motif but are gated by cyclic nucleotides and calcium, respectively. The three other families of potassium channel alpha subunits have distinct patterns of transmembrane domains. Slo family potassium channels, or BK channels have seven transmembrane domains (Meera et al.,
Proc. Natl. Acad. Sci. U.S.A
. 94(25):14066-71 (1997)) and are gated by both voltage and calcium or pH (Schreiber et al.,
J Biol. Chem
. 273:3509-16 (1998)). Another family, the inward rectifier potassium channels (Kir), belong to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or “two-pore”) contains two tandem repeats of this inward rectifier motif.
Potassium channels are typically formed by four alpha subunits, and can be homomeric (made of identical alpha subunits) or heteromeric (made of two or more distinct types of alpha subunits). In addition, potassium channels made from Kv, KQT and Slo or BK subunits have often been found to contain additional, structurally distinct auxiliary, or beta, subunits. These subunits do not form potassium channels themselves, but instead they act as auxiliary subunits to modify the functional properties of channels formed by alpha subunits. For example, the Kv beta subunits are cytoplasmic and are known to increase the surface expression of Kv channels and/or modify inactivation kinetics of the channel (Heinemann et al.,
J Physiol.
493:625-633 (1996); Shi et al.,
Neuron
16(4):843-852 (1996)). In another example, the KQT family beta subunit, minK, primarily changes activation kinetics (Sanguinetti et al.,
Nature
384:80-83 (1996)).
Slo or BK potassium channels are large conductance potassium channels found in a wide variety of tissues, both in the central nervous system and periphery. They play a key role in the regulation of processes such as neuronal integration, muscular contraction and hormone secretion. They may also be involved in processes such as lymphocyte differentiation and cell proliferation, spermatocyte differentiation and sperm motility. Three alpha subunits of the Slo family have been cloned, i.e., Slo1, Slo2, and Slo3 (Butler et al.,
Science
261:221-224 (1993); Schreiber et al.,
J Biol. Chem
., 273:3509-16 (1998); and Joiner et al.,
Nature Neurosci
. 1: 462-469 (1998)). These Slo family members have been shown to be voltage and/or calcium gated, and/or regulated by intracellular pH.
Certain members of the Kv family of potassium channels were recently renamed (see Biervert, et al.,
Science
279:403-406 (1998)). KvLQT1 was re-named KCNQ1, and the KvLQT1-related channels (KvLR1 and KvLR2) were renamed KCNQ2 and KCNQ3, respectively. More recently, a fourth member of the KCNQ subfamily was identified (KCNQ4) as a channel expressed in sensory outer hair cells (Kubisch, et al.,
Cell
96(3):437-446 (1999)).
KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassium channels associated with benign familial neonatal convulsions (“BFNC”), a class of idiopathic generalized epilepsy (see, Leppert, et al.,
Nature
337:647-648 (1989)). These channels have been linked to M-current channels (see Wang, et al.,
Science
282:1890-1893 (1998)). The discovery and characterization of these channels and currents provides useful insights into how these voltage dependent (Kv) potassium channels function in different environments, and how they respond to various activation mechanisms. Such information has now led to the identification of modulators of KCNQ2 and KCNQ3 potassium channels or the M-current, and the use of such modulators as therapeutic agents. The modulators are the subject of the present invention.
Bioactive compounds based on a benzanilide motif are known for the treatment of circulatory disturbances (Arita et al., U.S. Pat. No. 5,958,944), fungal infections (Baker et al., U.S. Pat. No. 4,845,107), inflammation (Beeley et al., U.S. Pat. No. 5,340, 827) and ulcers and bacterial infections (Nishino et al., 5,859,032). The previous benzanilides do not include the 2-substituted-5-aminopyridine substructure found in the compounds of the present invention. Moreover, none of the known benzanilide analogues are disclosed to modulate potassium channels or to be of use in treating conditions involving the modulation of potassium channels.
SUMMARY OF THE INVENTION
The present invention provides compounds which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases, and as neuroprotective agents (e.g., to prevent stroke and the like)).
In one aspect, the present invention provides compounds having a structure according to Formula I:
in which the symbol Ar
1
represents a member selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl. The letter X represents a member selected from the group consisting of O, S and N—R
1
, in which R
1
is H, (C
1
-C
8
)alkyl, substituted (C
1
-C
8
)alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C
1
-C
4
)alkyl, substituted aryl(C
1
-C
4
)alkyl, CN, —C(O)R
2
, —OR
3
, —C(O)NR
3
R
4
, or —S(O)
2
NR
3
R
4
. The symbol R
2
represents a member selected from the group consisting of (C
1
-C
8
)alkyl, substituted (C
1
-C
8
)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted heterocyclyl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C
1
-C
4
)alkyl and substituted aryl(C
1
-C
4
)alkyl. R
3
and R
4
are each members independently selected from the group consisting of hydrogen, (C
1
-C
8
)alkyl, substituted (C
1
-C
8
)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, h
Gross Michael F.
McNaughton-Smith Grant A.
Wickenden Alan D.
Davis Zinna Northington
Icagen Inc.
Townsend and Townsend / and Crew LLP
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