Imidazo isothiazoles

Much has been said about the application of this heterocyclic system in supramolecular chemistry and in materials chemistry, particularly in the preparation of organic conductors and superconductors. It should not be forgotten however that heterocyclic compounds in general are extremely important medicinal compounds. Although medicinal applications of this heterocyclic system have been rare in the years since CHEC-II(1996), some have been reported. Townsend and co-workers have described the preparation of imidazo[4,5-r/ isothiazole nucleosides 174-177 and have demonstrated their properties as antiproliferative and antiviral analogues of the antibiotic nebularine 172 and the highly cytotoxic 6-methylpurine nucleoside 173 <1997JME771>. 

Ring expansion of the bicyclic isothiazole (698) occurred upon treatment with cyanide ion to give the imidazo[l,2-c][l,3]thiazine (699). The mechanism involves initial ring opening by attack on sulfur, and then ring closure. The anion of methyl propiolate also causes the same type of rearrangement (79TL1281). 

Scheme 71 Synthesis of imidazo[4,5-d]isothiazole-containing nucleosides...

Antiviral and antitumor. Purine nucleosides analogues have been investigated as antitumor and antiviral agents. Bioisosteric derivatives of nucle-obases have been proposed, hi particular, as the sulphur atoms is analogous to a - CH = CH - group because of its steric and electronic properties, different imidazo[4,5-d]isothiazoles 292 (R = H, Me R = H, SMe, SBu) have been synthesised. All compounds were cytotoxic at micromolar concentrations, but showed no antiviral activity on human cytomegalovirus and herpes simplex virus type 1 [96]. The nucleoside analogue 12 was also prepared, but showed none antiviral activity nor cytotoxicity [10]. 

The oxazolyloxazoline (206) rearranged on heating in toluene to give the imidazo[5,l-Z)]oxazole (207) <75JOC1521>. Treatment of (208) with DMAD at 110°C gave pyrazolo[l,5-Z ]isothiazole derivatives (209) <82ZOR2626>. 

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