Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-01
2001-02-06
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S157000, C546S156000
Reexamination Certificate
active
06184231
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel 3-substituted-4-arylquinolin-2-one derivatives which are modulators of the large-conductance calcium-activated potassium (BK) channels and, therefore, useful in the protection of neuronal cells and diseases arising from dysfunction of cellular membrane polarization and conductance. The present invention also provides a method of treatment with the novel substituted quinolin-2-one derivatives and to pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are largely regulated by voltage, cell metabolism, calcium and receptor mediated processes. [Cook, N. S.,
Trends in Pharmacol. Sciences
(1988), 9, 21; and Quast, U., et al.,
Trends in Pharmacol. Sciences
(1989), 10, 431]. Calcium-activated potassium (K
ca
) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of K
Ca
channels is regulated by intracellular [Ca
2+
], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K
+
solutions, K
Ca
channels are divided into three subclasses: large conductance (BK)>150 pS; intermediate conductance 50-150 pS; small conductance<50 pS. Large-conductance calcium-activated potassium (Maxi-K or BK) channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. et al.,
Pflugers Archiv
. (1987) 408,98; Baro, I., et al.,
Pflugers Archiv
. (1989) 414 (Suppl. 1), S168; and Ahmed, F. et al.,
Br. J. Pharmacol
. (1984) 83, 227].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and maintain the transmembrane voltage near the K
+
equilibrium potential (E
k
) of about −90 mV. It has been shown that opening of potassium channels shift the cell membrane potential towards the equilibrium potassium membrane potential (E
k
), resulting in hyperpolarization of the cell. [Cook, N. S.,
Trends in Pharmacol. Sciences
(1988), 9, 21]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. BK channels which are regulated by both voltage and intracellular Ca
2+
act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells.
A range of synthetic and naturally occurring compounds with BK opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a BK channel opener using lipid bi-layer technique [International Patent application WO 93/08800, published May 13, 1993]. 6-Bromo-8-(methylamino) imidazo[1,2-a]pyrazine-2-carbonitrile (SCA-40) has been described as a BK channel opener with very limited electrophysiological experiments [Laurent, F. et al.,
Br. J. Pharmacol
. (1993) 108, 622-626]. The flavanoid, Phloretin has been found to increase the open probability of Ca
2+
-activated potassium channels in myelinated nerve fibers of
Xenopus laevis
using outside-out patches [Koh, D-S., et al.,
Neuroscience Lett
. (1994) 165, 167-170].
In European patent application EP-477,819 published Jan. 4, 1992 and corresponding U.S. Pat. No. 5,200,422, issued Apr. 6, 1993 to Olesen, et al., a number of benzimidazole derivatives were disclosed as openers of BK channels by using single-channel and whole-cell patch-clamp experiments in aortic smooth muscle cells. Further work was reported by Olesen, et al., in
European J. Pharmacol
., 251, 53-59 (1994).
A number of substituted oxindoles have been disclosed as openers of BK channels by P. Hewawasam, et al., in U.S. Pat. No. 5,565,483, issued Oct. 15, 1996.
Sit, et al., in International Patent Application WO 98/23273, published Jun. 4, 1998, and corresponding U.S. Pat. No. 5,892,045, issued Apr. 6,1999, disclosed a series of 4-aryl-3-hydroxyquinolin-2-one derivatives, while Hewawasam, et al., in International Patent Application WO 99/09983, published Mar. 4, 1999, disclosed a series of 4-aryl-3-aminoquinolini-2-one derivatives which are openers of BK channels and useful in the treatment of disorders sensitive to potassium channel opening activity.
E. S. Hamanaka in U.S. Pat. No. 5,565,472, issued Oct. 15, 1996, discloses a number of 4-aryl-3-(heteroarylureido)-1,2-dihydro-2-oxo-quinoline derivatives which are inhibitors of acyl coenzyme A; cholesterol acyltransferase and are useful as hypolipidemic and antiatherosclerosis agents.
It is the object of the present invention to provide novel compounds that will modulate potassium channels, in particular, large-conductance calcium-activated potassium (BK) channels which will be useful in diseases arising from dysfunction of cellular membrane polarization and conductance.
SUMMARY OF THE INVENTION
The present invention provides novel 3-substituted-4-arylquinolin-2-one derivatives having the general formula
wherein R, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined below, or a non-toxic pharmaceutically acceptable salt thereof which are openers of the large conductance calcium-activated K
+
channels also known as Maxi-K or BK channels. The present invention also provides pharmaceutical compositions comprising said quinolin-2-one derivatives and to the method of treatment of disorders sensitive to potassium channel opening activity such as ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction and urinary incontinence.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel 3-substituted-4-arylquinolin-2-one derivatives which are potent openers of the high conductance, calcium-activated K
+
-channels (BK channel) and which have the formula
wherein
R and R
1
each are independently hydrogen or methyl;
R
2
, R
3
and R
4
each are independently hydrogen, halogen, nitro or trifluoromethyl, provided R
2
, R
3
, and R
4
are not all hydrogen;
R
5
is bromo, chloro or nitro;
R
6
is hydrogen or fluoro;
n is an integer from 0 to 6;
m is an integer of 0 or 1; and
R
7
is CH
3
, —CRR
1
OH, —CHO, —C═NOH, —COCH
3
or aryl optionally substituted by one or two substituents selected from the group consisting of halogen, hydroxy, methoxy, amino, acetylamino and trifluoromethyl;
or a nontoxic pharmaceutically acceptable salt thereof.
The present invention also provides a method for the treatment or alleviation of disorders associated with BK channels, such as ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, urinary incontinence and especially male erectile dysfunction which comprises administering together with a conventional adjuvant, carrier or diluent a therapeutically effective amount of a compound of formula I or a nontoxic pharmaceutically acceptable salt thereof.
The term “nontoxic pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic base addition salts with inorganic bases. Suitable inorganic bases such as alkali and alkaline earth metal bases include metallic cations such as sodium, potassium, magnesium, calcium and the like. Unless otherwise specified, the term “halogen” as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term “halide” is intended to include bromide, chloride and iodide anion.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms including hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. The products may be true solvates, while in other cases, the products may merely retain adventitious s
Hewawasam Piyasena
Starrett, Jr. John E.
Algieri Aldo A.
Bristol-Myers Squibb
Huang Evelyn Mei
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