Aryl Substituted Pyrazole, Imidazole, Oxazole, Thiazole and Pyrrole and Use Thereof

WO 00/57877 PCT USOO / 07944 aryl substituted pyrazole, imidazole, oxazole, thiazole and pyrrole and its use BACKGROUND OF THE INVENTION Field of the Invention The present invention is in the field of medicinal chemistry. In particular, the invention relates to aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles, and these compounds are found to be anticonvulsants and act as blockers for sodium (Na channels).

 

Related Background Art Several types of therapeutically useful drugs have been shown, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmic drugs such as propafenone and amorolone, and lamotrigine, phenytoin and card Maxim's anticonvulsants have a common mechanism of action that can be blocked or regulated. Na' channel activity (Catterall, Trends Pharmacol. Sci. 8: 57-65 (1987)). It is believed that each of these agents works by interfering with the rapid influx of Na' ions.

 

Recently, other Na' channel blockers, such as BW619C89 and rifacycline, have been shown to have neuroprotective effects in animal models of holistic and focal ischemia and are currently being used in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269: 854 - see, for example, J. Am. Chem. Soc. 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 reducing the extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. The study has 00/57877 PCT / USOO / 07944 -2 showing that, unlike glutamate receptor antagonists, Na' channel blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12: 430-439 (1992)). As a result, they offer advantages in the treatment of certain types of stroke or neuronal trauma, which are most damaging to the white matter bundle.

 

Another example of clinical use of Na channel blockers is riluzole. This drug has been shown to prolong the survival of some patients with ALS (Bensim et al, New Engl. J. Med. 330:585-591 (1994)) and subsequently approved by the FDA for the treatment of ALS. In addition to the above clinical uses, carbamazepine, lidocaine and phenytoin are sometimes used to treat neuropathic pain, such as trigeminal neuropathy, diabetic neuropathy and other forms of neurological damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16: 309). - 316 (1995)) and carbamazepine and lamotrigine have been used to treat manic depression (Denicott et al, J. Clin. Psychiatry 55: 70-76 (1994)). In addition, based on many similarities 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 suggested that tinnitus should be considered a form of chronic pain sensation (Simpson, J. J. and Davies, E. W. Tip. 20: 12-18 (1999)). Indeed, lidocaine and carbamazepine have been shown to be effective in treating tinnitus (Majumdar, B. et al., Clin.

 

Otorhinolaryngology. 8:175-180 (1983); Donaldson, I. Laryngol. Whisper 95: 947-951 (1981)).

 

It has been determined that at least five to six sites on a pressure sensitive Na channel specifically bind to a neurotoxin (Catterall, Science 242: 50-61 (1988)). Studies have further shown that its role is mediated by Na'-channel therapeutic antiarrhythmic drugs, anticonvulsants and local anesthetics, by interacting with the inner side of the Na' channel and allosterically inhibiting the neurotoxin receptor site 2 The interaction plays a role (Catterall, WA, Ann Rev. Pharmacol. Toxicol. 10: 15-43 (1980)).