Aryl substituted pyrazoles, and pyrroles, and the use thereof

Details Aryl substituted pyrazoles, and pyrroles, and the use thereof Aryl substituted pyrazoles, and pyrroles, and the use thereof

2000-03-24

2002-07-02

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S403000, C548S356100, C548S373100, C548S377100

Reexamination Certificate

active

06414011

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 aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles, 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)).
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 (Bensim 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)). 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;
10:154-3 (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.
Dirmmock 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.
Pevarello et al., (
J. Med. Chem.
41:579-590 (1998)) discloses 2-[(arylalkyl)amino]alkanamide derivatives represented by the following Formula:
where R
1
is chloro, fluoro, trifluoromethyl, R
2
is chloro, cyano, fluoro, methyl, nitro, methoxy and trifluoromethyl, R
3
is chloro and fluoro and X is CH
2
O, a bond, CH
2
, CH
2
CH
2
, CH
2
S, CH
2
NH, OCH
2
, CH
2
CH
2
O, CH
2
CH
2
CH
2
O, CH
2
N(Me), NHCH
2
, CONH and CH═CH. The compounds are disclosed to be useful as anticonvulsants due to activity as sodium channel blockers.
PCT International Published Application WO 98/52940 discloses substituted pyrazoles of the following Formulae:
where R
1
is alkylsulfinyl, arylsulfinyl, alkylsulfonyl and acyl and R
3
is limited to pyridinyl, pyrimidinyl, quinolinyl, purinyl, C-attached malemides and pyridiones. The compounds are disclosed to be useful as p38 kinase inhibitors.
PCT International Published Application WO 98/50348 discloses substituted sulfonamides of the following Formula:
where Z is a heteroaryl group. The compounds are disclosed to be metalloproteinase inhibitors.
Japanese Patent Application JP 10168063 (CA 129:91737) discloses compounds of the following Formulae:
The compounds are described as microbiocides.
European Patent Application EP 446180 discloses substituted pyrazoles of the following Formula:
wherein X is oxygen and Y is OC
2
H
5
or OH. The compounds are disclosed as starting materials.
Radwan, S. M. (
Collect. Czech. Chem. Commun.
57(7): 1553-1558 (1992)) describes the synthesis of the compound of the following Formula:
Korshak, K. K., et al., (
Polym. Sci. USSR
(
Engl. Transl.
) 6: 1087, 1196-1198 (1964) and
J. Polym. Sci. Part A
3: 2425-2439 (1965)) describe the synthesis of the following compounds:
Stille et al., (
J. Polym. Sci. Part A
-1 6: 2317-2330 (1968)) describe the synthesis of the following compound:
Szmant et al., (
J. Am. Chem. Soc.
78: 4386-4389 (1956)) describes the following compound:
Grandberg et al. (
J. Gen. Chem. USSR
(
Engl. Transl
) 30: 1404-1408 (1960)) describe the synthesis of 3-(4-phenoxyphenyl)pyrazoles of the following Formula:
where R
1
is hydrogen or C(O)NH
2
. With R
1
hydrogen, the picrate salt was also prepared.
The following pyrazoles are part of the available chemical directory (ACD):
2-chloro-6-[4-(1H-pyrazol-5-yl)phenoxy]benzonitrile; 2-chloro-6-[4-(1-methyl-1H-pyrazol-5-yl)phenoxy]benzonitrile; 2-chloro-6-[4-[1-(4-chlorobenzoyl)-1H-pyrazol-5-yl]phenoxy]benzonitrile; 2-[4-(1-acetyl-1H-pyrazol-5-yl)phenoxy]-6-chlorobenzonitrile; 2-chloro-6-(4-[1-[(4-chlorophenyl)sulfonyl]-1H-pyrazol-5-yl]phenoxy)benzonitrile; 2-chloro-6-[4-[1-(methylsulfonyl)-1H-pyrazol-5-yl]phenoxy]benzonitrile; 2-chloro-6-[4-[1-(4-chlorophenyl)-1H-pyrazol-3-yl]phenoxy]benzonitrile; 3-(4-phenoxyphenyl)-1H-pyrazole; 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole; 3-[4-(4-methoxyphenoxy)phenyl]-1H-pyrazole; 3-[4-(phenylthio)phenyl]-1H-pyrazole; 3-[4-(phenylsulfonyl)phenyl]-1H-pyrazole; 5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazole; N1-phenyl-5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide; (4-chlorophenyl)[5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl]methanone; N1-(4-chlorophenyl)-5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide; [5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl](phenyl)methanone; 3-(2-chloro-4[4-chlorophenoxy])phenyl pyrazole; 1-phenylcarbamoyl-3-(2-chloro-4-[4-chlorophenoxy]phenyl pyrazole; 3-(2-chloro-4[4-chlorophenoxy])phenyl-1-(4-chlorophenylcarbamoyl)pyrazole; 3-(2-chloro-4[4-chlorophenoxyl]phenyl-1-(4-chlorobenzoyl)pyrazole; 1-(4-chlorobenzenesulfonyl-3-(2-chloro-4-[4-chlorophenoxy]phenylpyrazole; 1-(2,4-dichlorophenylsulfonyl)-3-dimethylamino-4-(4-phenoxyphenyl)

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