Imidazo thiazol-3-ones

The substituted imidazo-thiazole, dexamisole, has antidepressant properties and its isomer, levamisole, possesses anthelmintic and immunostimulant properties. Enantiomers of HA-966 (3-amino-l-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects (+)-HA-966 is a selective glycine/A-methyl-o-aspartate receptor antagonist, but (-)-HA-966 is a potent i-butyrolactone-Uke sedative." A comparison of (+) and (-)-3-methoxycypro-heptadine shows that aU of the anticholinergic activity of the ( )-3-methoxycyproheptadine resides solely in the dextrorotatory enantiomer, while the antiserotonin activity resides in the levorotatory enantiomer." ... 

Some work was carried out to investigate the reaction of 1,2-diaza-l,3-butadienes 409 with 2-imidazolidinethione in methanol at room temperature. 5,6-Dihydro-imidazo[2,l-3]thiazol-3-ones 410 were formed in 27-62% yield (Equation 186) <1999T13423>. 

Substituted imidazo[2,l-3]thiazoles with a lactam ring derived from 2-iminothiazolidine-4-one 482 and from pyr-imidine-2,4,6-trione 483 and 6-substituted-2,3-dihydro-imidazo[2,l-3]thiazole with a bicyclic 2-indolinone system 125 were discovered as new cardotonic agents and showed a positive inotropic activity <1996EJM383, 1997EJM919>. 

Russian authors investigated this important reaction type to prepare a wide range of aryl-, alkyl-, and acyl-substituted imidazo[2,l-ft]thiazoles (70KGS508, 70KGS512 71KGS389). Several 2-mercaptoimidazoles react with a-halo ketones in one step directly to the bicyclic products 35 under reflux in butanol or ethanol followed by basification. Yields vary between 52 and 99%, but the two-step cyclization route requires isolation of the intermediates 34 and subsequent heating in phosphorus oxychloride. 

In another approaeh [88IJC(B)570], reaetion of 2-mereapto-4,5-di-p-tol-ylimidazole 43 with a-halo carboxylie acids enabled the synthesis of several imidazo[2,l-h]thiazoles. Acylative ring closure of 4,5-di-p-tolylimidazo-2-thioacetic acid (44, R = H) or 2-thiopropionic acid (44, R = Me) provides 5,6-di-p-tolylimidazo[2,l-h]thiazole-3(2//)-one (45, R = H) or its 2-methyl analog (45, R = Me). The synthesis of annelated imidazo[2,l-h]thiazoles (e.g., 46) can be achieved in one step by reaction of 2,3-dichloroquinoxaline with 43. The intramolecular eyelization of l-vinylimidazole-2-thiones to 2,5-dimethyl-3,6-arylimidazo[2,l-h]thiazoles with excellent yield has been reported (93T6619). 

Table VII lists biological activities that have been found for some aromatic azapentalenes. Among these, imidazo[2,l-6]thiazoles have probably been most studied, and this has partly followed the discovery454 that a tetrahydro derivative 480 possessed marked anthelmintic activity. This compound is marketed as Tetramisole (or as the L-isomer, Levamisole) and is at present one of the most effective agents for the treatment of roundworm infestations. Anthelmintic activity has been found for aromatic imidazo[2,l-6]thiazoles (Table VII), and it has been suggested331 that a 6-aryl substituent is necessary for activity in this series.

A solution of 2 parts of DL-2-(acetylimino)-3-[2-hydroxy-2-(2-thienyl)ethyl]thiazoline in 16 parts of thionylchloride and 45 parts chloroform is stirred and refluxed for one hour. After cooling the whole is extracted with water. The acid aqueous solution is separated, washed with toluene, alkalized with ammonium hydroxide solution and extracted with chloroform. The extract is dried over magnesium sulfate and evaporated. The oily residue is dissolved in 40 parts boiling 2-propanol. To this warm solution is added a warm solution of an equivalent quantity of oxalic acid dihydrate in 2-propanoL After cooling to room temperature, the precipitated oxalate is filtered off and dried in vacuum, yielding DL-5,6-dihydro-6-(2-thienyl)imidazo[2,l-b]thiazole oxalate MP 192°-193°C. 

Many examples of imidazo[2,l-/7]thiazol-3(2//)-one (11), imidazo[5,l-i>]thiazol-3(2//)-one (14), and their partially (12,15) and completely saturated (13) derivatives are known. Interesting biological activities have been found. 

The easy ring-opening quality of hexafluoro-1,2-epoxypropane in the presence of a nucleophile has been used to accomplish the synthesis of imidazo[2,l-fe]thiazol-3(2//)-one. Thus, the sodium salt of 4,5-diphenylimidazolyl-2-thione (16, R = = Ph) reacts with hexafluoro-... 

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