Substituted 5- and 6-quinoxalinecarboxylic acids and their tuberculostatic activity

Abstract

Condemation of aliphatic and aliphatic-aromatic a-diketones, and of substituted benzils with 2,3-and 3,4-diaminobenzoic acids and with 4,5-diamino-2-hydroxybenzoic acid gave 74 5-and 6-quinoxalinecarboxylic acids, with the same or different alkyls and aryls as substituents at positions 2 and 3_ The compounds with different substituents at positions 2 and 3 were resolved into positional isomers. Their structures were determined by means of the dipole moments. The compounds were tested for tuberculostatic activity. Some exhibited it in vitro (LI, L VII), but failed ill riro.A ~igJlificant tuberculostatic activity was demonstrated with some derivatives of quinoxaline and benzo[b Jquinoxaline 1 -3. The in vivo tests also showed a high activity, but their side effects and too firm binding to tissues 3 make them clinically unsuitable. Since the introduction of a carboxyl group into an organic compound u~ ually ,uppresses its affinity to tissues and speeds up its secretion, we have prepared variously substituted 5-and 6-quinoxalinecarboxyIic acids. Some of them have been described before, but were not te5ted bacteriologically.To synthetize them we used the general reaction of ex-diketones with aromatic o-diamines. The latter were 2,3 and 3,4-diaminobenzoic acids and 4,5-diamino--2-hydroxybenzoic acid. These were condensed with aliphatic, cycloaliphatic and aliphatic-aromatic ex-diketones, as well as with variously substituted benzils. These reactions proceeded smoothly and largely gave good yields. In most cases we used to advantage the method of van der Stellt and coworkers 4 , who heated an equimolar mixture of an ex-diketone and an o-diamino compound in acetic acid (method A).However, in using this method we sometimes obtained blackish products. In such ca~.es it proved rewarding to replace acetic acid by ethanol (method B). If the starting cx-diketone was at least partially soluble in water it was possible to use water acidified with hydrochloric acid (method C), as described by Perella and coworkers 5 • In the condensation of non-symmetrical cx-diketones (different R's) mixtures of positional isomers were formed. With only one exception, these were resolved by cry,tallization or column chromatography. However, demonstration of their structures was a problem. First we tried the synthetic method, attempting condensation of l-methyl-2-phenylethanedione with 4-nitro-5-aminosalicyclic acid and/or Collect:cn Czechoslovak Chern.

New Inhibitors of Bacterial Protein Synthesis from a Combinatorial Library of Macrocycles

“…2,3-Dimethylquinoxaline-6-carboxylic acid was obtained from the hydrolysis of commercially available methyl 2,3-dimethylquinoxaline-6-carboxylate . 1,4-Dihydro-7-nitro-quinoxaline-2,3-dione-6-carboxylic acid was prepared from the nitration of 1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid using standard procedures . 6-(Chlorosulfonyl)-1,4-dihydroquinoxaline-2,3-dione and 7-(chlorosulfonyl)-6-methyl-1,4-dihydroxyquinoxaline-2,3-dione were prepared from a modification of a literature procedure using commercially available 1,4-dihydroquinoxaline-2,3-dione and 6-methyl-1,4-dihydroquinoxaline-2,3-dione, respectively …”

“…42 1,4-Dihydro-7-nitro-quinoxaline-2,3dione-6-carboxylic acid was prepared from the nitration of 1,4dihydroquinoxaline-2,3-dione-6-carboxylic acid using standard procedures. 43 6-(Chlorosulfonyl)-1,4-dihydroquinoxaline-2,3dione and 7-(chlorosulfonyl)-6-methyl-1,4-dihydroxyquinoxaline-2,3-dione were prepared from a modification of a literature procedure using commercially available 1,4-dihydroquinoxaline-2,3-dione and 6-methyl-1,4-dihydroquinoxaline-2,3-dione, respectively. 44 Preparation of 1,4-Dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic Acid (for the Preparation of 10).…”