Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-21
2001-08-28
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S238200, C514S241000, C514S247000, C514S269000, C514S311000, C514S315000, C514S459000, C514S590000, C544S111000, C544S158000, C544S162000, C544S215000, C544S238000, C546S175000, C546S332000, C548S567000, C548S569000, C549S426000, C549S487000, C549S491000, C564S034000, C564S035000
Reexamination Certificate
active
06281211
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 substituted semicarbazides and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na
+
) channels.
2. Related Background 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 et al.,
J. Pharmacol. Exp. Ther
. 269:854-859 (1994); Brown et al.,
British J. Pharmacol
. 115:1425-1432 (1995);
SCRIP
1870:8 (1993);
SCRIP
1773:14 (1992)).
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 et al.,
J. Clin. Psychiatry
55: 70-76 (1994)).
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, anticonvuisants 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)).
PCT International Published Application WO96/40628 discloses semicarbazones represented by the following Formula:
where R
1
-R
4
are independently hydrogen, halogen, C
1-9
alkyl, C
3-9
cycloalkyl, cyano, C
1-9
alkoxy, or C
6-10
aryloxy; R
5
is hydrogen, C
1-9
alkyl, C
3-9
cycloalkyl, or C
6-10
aryl; and X is oxygen or sulfur. The compounds are disclosed to be useful as anticonvulsants. However, it was not suggested or implicated that semicarbazides, which can be prepared by reduction of the semicarbazones, also will act as anticonvulsants.
Dimmock et al.,
J. Med. Chem
. 39:3984-3997 (1996) discloses (aryloxy)aryl semicarbazones that displayed anticonvulsant activities when administered intraperitoneally to mice or orally to rats. However, it was not suggested or implicated that semicarbazides, which can be prepared by reduction of the semicarbazones, also will act as anticonvulsants.
SUMMARY OF THE INVENTION
The present invention is related to the surprising discovery that novel substituted semicarbazides represented by Formula I are anticonvulsants and act as blockers of sodium (Na
+
) channels. Although the semicarbazides of Formula I can be prepared by reduction of the corresponding semicarbazones, semicarbazides and semicarbazones are two different classes of compounds. Semicarbazide is a base due to the presence of the basic N-1 nitrogen. Semicarbazone is not a base but the NH group on N-2 nitrogen is slightly acidic. The C═N double bond in semicarbazone make it a relatively rigid molecule. The C—N single bond in semicarbazide make it a relatively non-rigid molecule. Therefore it is a surprising discovery that semicarbazides of this invention as represented by Formula I are anticonvulsants and act as blockers of sodium (Na
+
) channels, similar to semicarbazones. 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), 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.
A first aspect of the present invention is directed to the novel substituted semicarbazides of Formula I.
A second aspect of the present invention is directed to the novel compounds of Formula I as blockers of sodium channels.
A third 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 neurodegenerative conditions; treating, preventing or ameliorating manic depression; treating local anesthesia, arrhythmias, and convulsion by administering a compound of Formula I to a mammal in need of such treatment.
A fourth 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.
A fifth aspect of the present invention is directed to methods for preparing novel compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention arises out of the discovery that novel substituted semicarbazides of Formula I are anticonvulsants and act as blocker of the Na
+
channel. 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 novel substituted semicarbazides represented by Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R
1
and R
2
are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
R
3
, R
4
, R
5
and R
6
are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R
3
and R
4
is defined as above, and R
5
and R
6
together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine;
A
1
and A
2
are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;
X is one of O, S, NR
7
, CH
2
, C(O), NR
7
C(O), C(O)NR
7
, SO, SO
2
or a covalent bond; where
R
7
is hydrogen, alkyl, cycloalkyl, alkenyl, alky
Cai Sui Xiong
Hong-Bae Soo
Lan Nancy C.
Covington Raymond
Euro-Celtique S.A.
Kight John
Sterne Kessler Goldstein & Fox P.L.L.C.
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