Nitrogen compounds benzoxazines

The 3,4-dihydro-22/-l,3-benzoxazin-4-one derivative DRF-2519 587, bearing a 2,4-thiazolidinedione moiety in the side chain attached to the nitrogen atom, proved to be an activator of the a- and y-types of the peroxisome proliferator-activated receptors (PPAR-a and -7), which endowed it with antidiabetic and hypolipidemic potential. Compound 587 demonstrated significant plasma glucose-, insulin-, and lipid-lowering activity in mice and improvement in lipid parameters in fat-fed rats <2006BMC584>. 

Reaction of unsaturated 5(4//)-oxazolones with bis(nucleophiles) opens the way for the preparation of diverse heterocyclic compounds depending on the nucleophilic atoms of the reagent. First, if we consider nitrogen-containing bis(nucleo-philes), the reaction of anthranilic acid with unsaturated oxazolones 550 gives rise to substituted 3,l-benzoxazin-4-ones 551 (Scheme 7.174). " °... 

However, Aae can still be used in suitable cases as an indication of conformation, particularly for polycyclic compounds. Thus Aae measurements on TV-CH2X protons may be used to establish the cis or trans nature of the ring fusion in 1,3-heterocyclic systems. For example, the trans-fused perhydro-pyrido[3,2,l-iJ][3,l]benzoxazine (21) shows Aae 0.84 ppm, indicative of the anti-coplanar CH-nitrogen lone-pair geometry, whereas the cis-fused isomer (22), in which the nitrogen lone pair bisects the CH2 group, shows Aae 0.12 ppm.45... 

A series of benzoxazines (131-139) were isolated [117] from fermentation broth of S. rimosus. These compounds were found to inhibit bacterial histidine kinase and were produced by a controlled cultivation with added NaBr and Nal. As mentioned above, streptopyrol (131) inhibits the nitrogen regulator II histidine kinase from Escherichia coli with IC o of 20 pM and exhibits antimicrobial activity against a wide range of bacteria and fungi. 

Reaction of phenols and hexahydro-l,3,5-triazines at 150°C also provides access to dihydro-1,3-benzoxazines (272) (Equation (24)). Similar constructions use hexamethylenetetramine, rather than hexahydro-l,3,5-triazines, but now the products are 3-benzyl derivatives (e.g. 273) (Equation (25)) <85ZOR2243>. It seems likely that, in these reactions, the nitrogen-containing reagents act as sources of methylenimine, which convert the phenols into the corresponding benzylamines. Further reactions with more methylenimine then results in cyclization if so these preparations are closely related to those which employ hydroxybenzylamines and carbonyl compounds. 

---