Quinolone analogues 6 [1‐5]. Synthesis of 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

Abstract

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.

Quinolone Analogues 12: Synthesis and Tautomers of 2‐Substituted 4‐Quinolones and Related Compounds

“…In previous articles , we reported the synthesis of the 1‐methylpyridazino[3,4‐ b ]quinoxalines 1a , 1b , 1c , 1d , 1e , 1f , 1g , 1h as candidates of antibacterial quinolone analogues (Chart ). The 3‐alkyl 1c , 1d , 1e , 3‐H 1f , and 3‐halogeno 1g , 1h derivatives were found to have antifungal and/or antibacterial activities ,, whereas the 3‐amino 1i , 1j and 3‐heteroaryl 1k , 1l , 1m derivatives were clarified to possess no antibacterial and antifungal activities . Thereafter, we converted the target ring system of the pyridazino[3,4‐ b ]quinoxalin‐4‐(1 H )‐one into the 4‐quinolone in the study to search for more potent antimicrobial agents.…”

Quinolone analogues 9. Synthesis of 7‐methylsulfanyl‐ and 7‐methanesulfonylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

“…Since the antibacterial activities of the 3-carboxyl derivatives 1 and 2 were not so good, the 3-substituent was converted into various functional groups in order to search for potent homologues, leading to the synthesis of compounds 3-7. As the result, the 3-alkyl, 3-H, and 3-halogeno derivatives 3-5 showed good antibacterial and antifungal activities [3][4][5][6]9] (Tables 1 and 2), while the 3-heteroaryl and 3-amino derivatives 6 and 7 did not exhibit antimicrobial activities to microorganisms shown in Tables 1 and 2. Thus, the 3alkyl, 3-H, and 3-halogeno derivatives 3-5 were found to be excellent candidates in the C3-homologues.…”

“…In previous papers [1][2][3][4][5][6][7][8], we reported the synthesis of the 1-methylpyridazino [3,4-b]quinoxalines 1-7 as candidates of antimicrobial quinolone analogues (Chart 1). Since the antibacterial activities of the 3-carboxyl derivatives 1 and 2 were not so good, the 3-substituent was converted into various functional groups in order to search for potent homologues, leading to the synthesis of compounds 3-7.…”

Quinolone Analogs 13: Synthesis of Novel 1,1′‐(2‐Methylenepropane‐1,3‐diyl)di(4‐quinolone‐3‐carboxylate) and Related Compounds

“…In previous papers , we reported the synthesis and biological activities of the 1‐alkyl‐4‐oxopyridazino[3,4‐ b ]quinoxalines 1 as candidates of antibacterial quinolone analogs (Chart ), some of which showed good antibacterial, antifungal, and/or algicidal activities . To search for biologically active compounds, we have then changed the target ring system from 4‐oxopyridazino[3,4‐ b ]quinoxaline to 4‐oxoquinoline such as quinolone antibacterials.…”