Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-08
2002-11-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S618000, C514S617000, C514S622000, C514S620000, C514S621000, C514S249000, C514S252020, C514S256000, C514S258100, C514S259400, C514S234800
Reexamination Certificate
active
06479484
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 substituted 2-aminoacetamides and the discovery that these compounds 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, 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)).
PCT International Published Application WO 90/14334 and WO 97/05102 disclose 2-(4-substituted)-benzylamino-2-methyl-propanamide derivatives represented by Formula I:
where n is 0-3; X is O, S, CH
2
or NH; each of R and R
1
independently is hydrogen, C
1-6
alkyl, halogen, hydroxy, C
1-4
alkoxy, or trifluoromethyl; each of R
2
, R
3
and R
4
independently is hydrogen, C
1-6
alkyl or C
3-7
cycloalkyl; The compounds are disclosed to be useful as antiepileptics, in the treatment of Parkinson's disease and as neuroprotective agents, e.g. preventing or treating neuronal loss associated with stroke, hypoxia, ischemia, CNS trauma, hypoglycemia or surgery, and in treating and preventing neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, Huntington's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), infarctual dementia and infections or inflammations in the brain; they can also be used as antidepressants, hypnotics, and antispastic agents and in treating ocular damage and retinopathy. However, their mechanism of action was not disclosed.
SUMMARY OF THE INVENTION
The present invention is related to 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. The present invention is also related to treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom by administering an effective amount of a compound of Formula II as described herein.
The present invention is also directed to the use of a compound of Formulae I or II 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 and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including chronic pain.
The present invention also is directed to the process for preparing novel substituted 2-aminoacetamide of Formula II.
A first aspect of the present invention is directed to the use of compounds of Formulae I or II as blockers of sodium channels.
A second 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 chronic pain; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating manic depression; inducing local anesthesia; and treating arrhythmias by administering a compound of Formulae I or II to a mammal in need of such treatment.
A number of compounds within the scope of the present invention are novel compounds. Therefore, a third aspect of the present invention is to provide novel compounds of Formula II, and to also provide for the use of these novel compounds for treating, preventing or ameliorating convulsions.
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 Formulae I or II 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 Formulae II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention arises out of the discovery that compounds of Formulae I and II act as blocker of the Na
+
channel. In view of this discovery, compounds of Formulae I and II are useful for treating disorders responsive to the blockade of sodium ion channels.
The compounds useful in this aspect of the present invention are substituted 2-aminoacetamides represented by Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R
1
R
2
, R
3
and R
4
are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
R
5
, R
6
and R
7
are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R
5
, is defined as above, and R
6
and R
7
together with the nitrogen atom to which they are attached form a heterocycle;
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 or O, S, NR
8
, CH
2
, C(O), NR
8
C(O), C(O)NR
8
, SO, SO
2
or a covalent bond; where
R
8
is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;
n is 0, 1, 2 or 3.
Preferred compounds falling within the scope of Formula II include compounds wherein A
1
and A
2
are both aryl moieties, preferably both phenyl moieties, that are each optionally independently substituted by one or two
Cai Sui Xiong
Lan Nancy C.
Wang Yan
Euro-Celtique S.A.
Habte Kahsay
Raymond Richard L.
Sterne Kessler Goldstein & Fox P.L.L.C.
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