Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-14
2002-10-22
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S418000, C548S450000, C548S469000
Reexamination Certificate
active
06469042
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel 3-fluoro-3-phenyl oxindole derivatives which are modulators of KCNQ potassium channels and are therefore useful in treating disorders responsive to the modulation of the potassium channels. The present invention also provides a method of treatment with the novel 3-fluoro oxindole derivatives and to pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Potassium (K
+
) channels are considered to be the most diverse class of ion channels and have several critical roles in cell function. This has been demonstrated in neurons where K
+
channels are responsible, in part, for determining cell excitability by contributing to membrane repolarization following depolarization, resting membrane potential, and regulation of neurotransmitter release. The M-current has long been described, by electrophysiology recording methods and by pharmacology, as a dominant conductance in controlling neuronal excitability. Pharmacological activation or suppression of M-currents by small molecules could have profound effects in controlling neuronal excitability. Recently, Wang et al. (1998,
Science,
282:1890-1893) reported that co-assembly of the KCNQ2 and KCNQ3 potassium channels underlies the native M-current in neurons.
Activation or opening of the KCNQ channel(s), particularly the KCNQ2 or KCNQ2/3 channel(s), mutated or wild type, may prove to be beneficial in increasing hyperpolarization of neurons, thereby resulting in protection from abnormal synchronous firing during a migraine attack. The present invention provides a solution to the problem of abnormal synchronous firing of neurons related to migraine headache by demonstrating that modulators, preferably openers, of KCNQ potassium channels increases hyperpolarization of neurons which protects against abnormal synchronous neuron firing involved in migraine attacks.
Although the symptom pattern varies among migraine sufferers, the severity of migraine pain justifies a need for vigorous, yet safe and effective, treatments and therapies for the great majority of cases. Needed in the art are agents that can be used to combat and relieve migraine (and diseases similar to and mechanistically related to migraine), and even prevent the recurrence of migraine. Also needed are anti-migraine agents which are effective in the treatment of acute migraine, as well as in the prodrome phase of a migraine attack. Thus, a clear goal in the art is to discover new, safe, nontoxic and effective anti-migraine compounds for use as drugs, and in anti-migraine compositions and treatments.
Because migraine afflicts a large percentage of the population, there is a need to discover compounds and agents that are useful in therapeutics and treatments, and as components of pharmaceutical compositions, for reducing, ameliorating, or alleviating the pain and discomfort of migraine headache and other symptoms of migraine. The present invention satisfies such a need by providing compounds that function as openers of the KCNQ family of potassium channel proteins to serve as anti-migraine agents or drugs and to comprise compositions to treat migraine, as described herein.
A number of substituted oxindoles have been disclosed as neuroanabolic agents by H. Kuch et al. in U.S. Pat. No. 4,542,148, issued Sep. 17, 1985 and U.S. Pat. No. 4,614,739, issued Sep. 30, 1986.
3-Substituted oxindole derivatives with utility as openers of the large conductance calcium-activated potassium channels have been disclosed by Hewawasam, P; Meanwell, N. A.; and Gribkoff, V. K. in U.S. Pat. No. 5,565,483, issued Oct. 15, 1996 and U.S. Pat. No. 5,602,169, issued Feb. 11, 1997, both of which are disclosed to be useful in the treatment of disorders that are responsive to the opening of the large conductance calcium-activated potassium channels, also called maxi-K channels. Because of their voltage and calcium dependence, maxi-K channels are distinct from KCNQ potassium channels, which are only voltage dependent. In addition, the pharmacology and kinetics of maxi-K channels versus KCNQ channels are frequently quite different, and the large conductance or maxi-K channels are responsive to the opener compounds specifically disclosed in U.S. Pat. No. 5,565,483. Thus, the compounds and their uses described in these patents are distinct from those of the present invention.
SUMMARY OF THE INVENTION
The present invention provides novel 3-fluoro oxindole derivatives having the general Formula I
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and Y are as defined below, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels. The present invention also provides pharmaceutical compositions comprising said 3-fluoro oxindole derivatives and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel 3-fluoro oxindole derivatives which are modulators of the KCNQ potassium channels and which have the general Formula I
wherein
R
1
, R
2
, R
3
and R
4
each are independently hydrogen, C
1-4
alkyl, halogen, fluoromethyl, trifluoromethyl, phenyl, 4-methylphenyl or 4-trifluoromethylphenyl;
R
5
is C
1-6
alkyl optionally substituted with one to three same or different groups selected from fluoro and chloro, provided R
5
is not C
1-6
alkyl when Y is O;
Y is O or S; and
R
6
and R
7
each are independently hydrogen, chloro, bromo or trifluoromethyl.
The present invention also provides a method for the treatment or alleviation of disorders associated with KCNQ potassium channel polypeptides and, in particular, human KCNQ potassium channel polypeptides which are especially involved in reducing or alleviating migraine or a migraine attack, which comprises administering together with a conventional adjuvant, carrier or diluent a therapeutically effective amount of a compound of Formula I.
The term “C
1-6
alkyl” as used herein and in the claims means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 4-methylbutyl, hexyl and the like. The term “C
1-4
alkyl” as used herein and in the claims means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The term “halogen” as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine.
As the compounds of the present invention possess an asymmetric carbon atom at the 3-position of the oxindole ring, the present invention includes the racemate as well as the individual enantiomeric forms of the compounds of Formula I as described herein and in the claims. Preferred embodiments of compounds of Formula I are the racemate and the single enantiomer which includes mostly the one stereoisomer having a (+) optical rotation is most preferred. Mixtures of isomers of the compounds of the examples or chiral presursors thereof can be separated into individual isomers according to methods which are known per se, e.g. fractional crystallization, adsorption chromatography or other suitable separation processes. Resulting racemates can be separated into antipodes in the usual manner after introduction of suitable salt-forming groupings, e.g. by forming a mixture of diastereosiomeric salts with optically active salt-forming agents, separating the mixture into diastereomeric salts and converting the separated salts into the free compounds. The enantiomeric forms may also be separated by fractionation through chiral high pressure liquid chromatography columns, according to procedures described herein.
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, trihydrate, hemihydrate, tetrahydrate and the like. The products may be true solvates, while in other cases, the products may merely retain adventitious solvent or be a mixture of solvate pl
Dextraze Pierre
Dworetzky Steven I.
Gribkoff Valentin K.
Hewawasam Piyasena
Kinney Gene G.
Algieri Aldo A.
Bristol--Myers Squibb Company
Lambkin Deborah C.
Shiau Rei-Tsang
LandOfFree
Fluoro oxindole derivatives as modulators if KCNQ potassium... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Fluoro oxindole derivatives as modulators if KCNQ potassium..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fluoro oxindole derivatives as modulators if KCNQ potassium... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2941385