Pyrazine derivativesPyrazine derivatives R 0550 Quinolone Analogues. Part 6. Synthesis of 3-Halogeno-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-ones. -Title compounds (VII) are synthesized from N-oxides (I) in 6 steps. They are found to show antifungal activities in vitro. -(KURASAWA*, Y.; SATOH, W.; MATSUZAKI, I.; MAESAKI, Y.; OKAMOTO, Y.; KIM, H. S.; J. Heterocycl. Chem. 40 (2003) 5, 837-843; Sch. Pharm. Sci., Kitasato Univ., Minato, Tokyo 108, Japan; Eng.) -F. Santoso 12-163

The reaction of the quinoxaline N-oxides 7a,b with diethyl ethoxymethylenemalonate gave the 1-methylpyridazino [3,4-b]quinoxaline-4,4-dicarboxylates 8a,b, whose reaction with N-bromosuccinimide or N-chlorosuccinimide afforded the 3-halogeno-1-methylpyridazino [3,4-b]quinoxaline-4,4-dicarboxylates 9a-d. The reaction of compounds 9a-d with hydrazine hydrate resulted in hydrolysis and decarboxylation to provide the 3-halogeno-1-methylpyridazino[3,4-b]quinoxaline-4-carboxylates 10a-d, whose reaction with nitrous acid effected oxidation to furnish the 3-halogeno-4-hydroxy-1-methylpyridazino[3,4-b]quinoxaline-4-carboxylates 11a-d, respectively. The reaction of compounds 11a-d with hydrazine hydrate afforded the 3-halogeno-1-methylpyridazino[3,4-b]quinoxalin-4-ols 12a-d, whose oxidation provided the 3-halogeno-1methylpyridazino[3,4-b]quinoxalin-4(1H)-ones 6a-d, respectively. Compounds 6a-d had antifungal activities in vitro. J. Heterocyclic Chem., 40, 837 (2003). Introduction.In previous papers [1-5], we have reported the synthesis of the 1-alkylpyridazino[3,4-b]quinoxalin-4-ones 1-5 (Scheme 1) as candidates of antimicrobial quinolone analogues. Since the 3-carboxylic acid derivatives 1 [1] showed only weak antibacterial activities, we produced the methylene-inserted carboxylate and carboxylic acid derivatives 2a,b [2] and then the 3-alkyl derivatives 3 [3] and 4 [4]. In these modifications, we found that compounds 1 and 2 had similar antibacterial activities, but compounds 3 and 4 exhibited better antibacterial activity [5] than those of compounds 1 and 2.

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