Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-29
2002-01-01
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...
C546S307000
Reexamination Certificate
active
06335354
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to novel aminopyridines, and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na
+
) channels.
2. Related Art
Several classes of therapeutically useful drugs including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na
+
channel activity (Catterall, W. A.,
Trends Pharmacol. Sci
. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na
+
ions.
Recently, other Na
+
channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham el al.,
J. Pharmacol. Exp. Ther
. 269:854-859 (1994); Brown et al.,
British J. Pharmacol
. 115:1425-1432 (1995)).
The neuroprotective activity of Na
+
channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na
+
channel blockers prevent hypoxic damage to mammalian white matter (Stys et al.,
J. Neurosci
. 12:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Na
+
channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al.,
New Engl. J. Med
. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum,
Trends Pharmacol. Sci
. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott el al.,
J. Clin. Psychiatry
55: 70-76 (1994)). Furthermore, based on a number of similiarities between chronic pain and tinnitus, (Moller, A. R.
Am. J. Otol
. 18: 577-585 (1997); Tonndorf,
J. Hear. Res
. 28. 271-275 (1987)) it has been proposed that tinnitus should be viewed as a form of chronic pain sensation (Simpson, J. J. and Davies, E. W.
Tip
. 20: 12-18 (1999)). Indeed, lignocaine and carbamazepine have been shown to be efficacious in treating tinnitus (Majumdar, B. et al.
Clin. Otolaryngol.
8: 175-180 (1983); Donaldson, I.
Laryngol. Otol.
95: 947-951 (1981)).
It has been established that there are at least five to six sites on the voltage-sensitive Na
+
channels which bind neurotoxins specifically (Catterall, W. A.,
Science
242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na
+
channels, exert their action by interacting with the intracellular side of the Na
+
channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A.,
Ann. Rev. Pharmacol. Toxicol
. 10:15-43 (1980)).
SUMMARY OF THE INVENTION
The present invention is related to the discovery that aminopyridines represented by Formula I are anticonvulsants and act as blockers of sodium (Na
+
) channels.
The invention is also related with treating a disorder responsive to the blockade of sodium channels in a mammal suffering from excess activity of said channels by administering an effective amount of a compound of Formula I as described herein.
The present invention is also directed to the use of a compound of Formula I for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), for the treatment of tinnitus, as antimanic depressants, as local anesthetics, as antiarrhythmics, as anticonvulsants and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including both acute and chronic pain and migraine headache.
One aspect of the present invention is directed to the novel aminopyridines of Formula I.
Another aspect of the present invention is directed to the novel compounds of Formula I as blockers of sodium channels.
A further aspect of the present invention is to provide a method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating pain including acute and chronic pain, and neuropathic pain; treating, preventing or ameliorating convulsion and neurodegenerative conditions; treating, preventing or ameliorating manic depression; using as local anesthesics and anti-arlhythmics, and treating tinnitus by administering a compound of Formula I to a mammal in need of such treatment or use.
Also, an aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
Further, the present invention is directed to
3
H and
14
C radiolabeled compounds of Formula I and their use as radioligands for their binding site on the sodium channel.
Additional embodiments and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention arises out of the discovery that aminopyridines of Formula I act as blockers of Na
+
channels. In view of this discovery compounds of Formula I are useful for treating disorders responsive to the blockade of sodium ion channels.
The compounds useful in this aspect of the present invention are aminopyridines represented by Formula I:
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
R
1
is selected from thc group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, cycloalkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, alkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, and heterocyclosulfonyl, all of which can be optionally substituted;
R
2
is hydrogen or C
1-6
alkyl and R
3
is hydrogen, or R
2
and R
3
together form a bond;
R
4
is hydrogen or C
1-6
alkyl;
R
5
, R
6
, R
7
, and R
8
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, aminoalkyl, cyano, amide, carboxyalkyl, alkoxyalkyl. ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
X is one of O, S, NR
9
, or CH
2
, wherein R
9
is hydrogen or alkyl; and m is 0-3.
Preferably X is O or S, more preferably X is O.
One group of preferred compounds useful in the present invention are aminopyridines represented by Formula II:
a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
R
1
, R
4
-R
8
are as defined above, X is O or S and m is 0 or 1.
Preferably, R
1
is selected f
CoCensys Inc.
Davis Zinna Northington
Sterne Kessler Goldstein & Fox PLLC
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